Peptide Deformylase

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Current Medicinal Chemistry, 2015, 22, 214-236
214
Peptide Deformylase: A New Target in Antibacterial, Antimalarial and

Anticancer Drug Discovery
Jaiprakash N. Sangshetti1,*, Firoz A. Kalam Khan1 and Devanand B. Shinde2
1
2
Y. B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad-431001;
Department of Chemical Technology, Dr. B. A. M. University, Aurangabad-431004, India
Abstract Peptide deformylase (PDF) is a class of metalloenzyme responsible for catalyzing the removal of
the N-formyl group from N-terminal methionine following translation. PDF inhibitors are moving into new
phase of drug development. Initially, PDF was considered as an important target in antibacterial drug discovery; however genome database searches have revealed PDF-like sequences in parasites (P. falciparum)
and human, widening the utility of this target in antimalarial and anticancer drug discovery along with antibacterial. Using structural and mechanistic information together with high throughput screening, several types of chemical
classes of PDF inhibitors with improved efficacy and specificity have been identified. Various drugs like, GSK-1322322
(Phase II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. Developments in the
field have prompted us to review the current aspects of PDFs, especially their structures, different classes of PDF inhibitors, and molecular modeling studies. In nut shell, this review enlightens PDF as a versatile target along with its inhibitors
and future perspectives of different PDF inhibitors.
Keywords: Antibacterial, anticancer, antimalarial, clinical developments, peptide deformylase.

1. INTRODUCTION
The successful development of antibacterial drugs generated a misconception in the late 1960s and early 1970s that
infectious diseases had been conquered, resulting in a decrease in academic and industrial research in antibacterial
area. However, 40 years later, infectious diseases remain the
second-leading cause of death worldwide [1]. During the
past decades, many epidemiologists have reported that
pathogenic bacteria and parasites rapidly develop resistance
to medicines currently used for treatment in human infections [2]. The emergence of multi-drug resistance is of great
concern and has created a situation in which there are few or
no treatment options for infections with certain microorganisms [3]. Gram-negative bacteria like P. aeruginosa, K.
pneumoniae, S. maltophila and A. baumannii are posing the
most serious treatment challenges with increasing incidence
of drug resistant isolates, and also there are fewer active antibiotics available to treat infections caused by such organisms [4, 5]. Among Gram-positive pathogens, the drug resistant pathogens of greatest concern are S. aureus, S. epidermidis, E. faecium and E. faecalis [6, 7]. Also, the emergence
of multi-drug resistant of M. tuberculosis strains has made
many of the currently available antitubercular drugs (ATDs)
ineffective [8].
Due to the current global resistance crisis, search for new
antibacterial agents with activity against drug-resistant
pathogens should be a high priority for the academic and
industrial researchers. It is now widely accepted that the traditional screening methods are unlikely to generate new
*Address correspondence to this author at the Y. B. Chavan College of
Pharmacy, Dr. Rafiq Zakaria Campus, Rauza Baugh, Aurangabad-431001,
India; Tel:/Fax: +91-240-23801129; E-mail: jnsangshetti@rediffmail.com
1875-533X/15 $58.00+.00
promising molecules. Alternative strategies must therefore

be developed to find new drugs. One possible strategy is to
identify a molecular target at the outset and then to screen
the available libraries of chemical compounds, looking for
hits with potent inhibitory capacities in-vitro. In order to
address this strategy, the identification of good and novel
target is vital [2]. Therefore, identification of a new target
which is previously untapped will play a critical role in the
development of new antibacterial agents active against resistant pathogens [9]. It is important that such new target
should: (i) be present in most human pathogens (i.e., the inhibitors should have broad spectrum activity); (ii) be absent
in human cells; (iii) be part of an essential pathway in the
pathogens; (iv) not be inhibited by widely used anti-infective
agents; (v) be easy to assay in-vitro and in-vivo; (vi) be
highly specific for the pathogens and be non toxic to human
being; and (vii) not be result in the rapid acquisition of resistance [10]. The analysis of microbial genomes has revealed
an abundance of novel and potentially useful targets, but, so
far, little has been achieved from these efforts [11]. One target that has not received much attention until recently is peptide deformylase (PDF). PDF has been a possible target that
may fulfill all the above criteria essential for good target to
develop new antibacterial agents with novel mechanism of
action.
Recently, genome database searches have revealed eukaryotic PDF-like sequences in parasites, plants, and mammals [12]. Malaria is the worlds most serious tropical parasitic disease and accounts for 1-3 million deaths each year
[13]. The increasing incidences of malaria reflect the development of drug resistant strains of Plasmodium and justify
referring to malaria as a re-emerging disease [14, 15]. Recognizing the potential importance of P. falciparum peptide
2015 Bentham Science Publishers
Peptide Deformylase: A New Target
deformylase (PfPDF) as a drug target, new antimalarial

agents with novel mechanism of action can be developed.
More recently, the human (H. sapiens) mitochondrial peptide
deformylase (HsPDF) has been cloned and characterized [16,
17]. The discovery of HsPDF has raised the possibility for
the development of new cancer cell target. Advancements
and findings of these PDFs in bacteria, parasites and human
provide tremendous opportunities for discovery of new antibacterial, antimalarial and anticancer as peptide deformylase
inhibitors.
There are very few reports published regarding PDF biology and its suitability as drug target [18-21]. To the best
our knowledge, there is no comprehensive review with medicinal chemistry view and covering all current aspects of
peptide deformylase. In this review, the authors have discussed the potential of PDF inhibitors as a new class of antibacterial agents. This article also summarizes the potential of
PDF inhibitors as antimalarial and anticancer agents. We
have discussed all the recent PDF inhibitors reported and
also that are in preclinical and clinical phases.
2. PEPTIDE DEFORMYLASE
Peptide deformylase (PDF) is a class of metalloenzyme
and responsible for catalyzing the removal of the N-formyl
group from N-terminal methionine following translation.
Adam [22] was the first to demonstrate the presence of PDF
(EC 3.5.1.27) in crude bacterial extracts more than four decades ago. The process for bacterial protein synthesis (Fig. 1)
is initiated with N-formylmethionine (f-Met-tRNAi), which
is generated through enzymatic transformylation of methionyl-tRNA (Met-tRNAi) by formyl methionyl transferase
(f-Mett). The N-formyl group of the polypeptide (emerges
from ribosome after completion of elongation process) is
removed by the sequential action of peptide deformylase [23,
24]. Methionine amino peptidase (MAP; EC 3.4.11.18) then
removes the N-terminal methionine depending on the nature
of the second amino acid in the peptide chain [25]. Thus,
deformylation plays an important role in bacterial protein
maturation.
The molecular catalytic cycle of PDF proceeds as shown
in (Fig. 2). The step 1 represents the initial state of PDF as
found in the structures. In the next step the formylated peptide binds with enzyme, thereby replacing water (W2) by
Current Medicinal Chemistry, 2015, Vol. 22, No. 2
215
the carbonyl oxygen of the formyl group. The carbonyl

oxygen is polarized by hydrogen bonds to the amide of Leu91 and the side chain of Gln-50. This supports the nucleophilic attack of water (W1) (probably a deprotonated water)
on the carbonyl carbon of the formyl group that leads to the
transition state of the reaction as depicted in step 3. The
carbonyl oxygen is tetrahedrally ligated by the metal, carbonyl carbon, side chain amide of Gln-50, and main chain
amide of Leu-91. This arrangement of amide hydrogen bond
donors resembles the oxyanion hole in serine and cysteine
proteases for stabilizing the transition state. The absence of
ionizable groups in the oxyanion hole is well in line with the
broad pH-activity profile of PDF-Fe which is nearly constant between pH 6.1 and 11.2. The electronic state of the
attacked carbonyl carbon changes from sp2 to sp3 accompanied by a transition from the tetrahedral to a five-coordinate
metal center.
The proton of W1 is transferred with the help of Glu-133
to the amide at the N-terminus of the peptide, the added positive charge making the nitrogen suitable as a leaving group.
Subsequent bond cleavage leads to the ternary enzymeformate-peptide complex shown in step 4. Here, the formate
is bound to the five-coordinated metal center and the free Nterminus of the peptide is hydrogen bonded to Glu-133. The
reaction proceeds by dissociation of the peptide which leaves
an activated enzyme-formate complex as shown in step 5.
The existence of such a complex is consistent with biochemical data which show that PDF can transfer the formyl
group from one formyl peptide to another peptide by a
ping-pong mechanism. The reaction cycle closes with the
release of formate and the uptake of two water molecules,
W1 and W2. It is very likely that formate release proceeds
by attack of a water molecule on the metal rather than on the
formate carbon atom. Evidence comes from the lack of 17O
exchange during incubation of 17O formate in the presence of
PDF [26].
Removal of the formyl group from polypeptide by PDF is
a necessary activity for prokaryotic cell viability [27]. This
activity was not believed to be important in eukaryotic cells
until recently, because nuclear encoded proteins are not Nformylated [17]. However, in eukaryotes, mitochondrial protein synthesis may also involve the formylation and deformylation process. This is evidenced by the presence of the
enzyme machinery to perform these activities in mammals
Fig. (1). Initiation of protein synthesis by methionine and role of PDF. Abbreviation: Met, Methionine; tRNAi, Initiator transfer RNA; fMett, Formyl methionyl transferase; aa-tRNAe, Amino acid elongation transfer RNA.
216 Current Medicinal Chemistry, 2015, Vol. 22, No. 2
Sangshetti et al.
Fig. (2). Proposed molecular catalytic mechanism of PDF. Abbreviation: W1 and W2, Water molecules.
and among other eukaryotes [28, 29]. PfPDF is found in the

apicoplast, an essential multimembrane-surrounded organelle. Bracchi-Ricchard et al. [30] have cloned the nuclear
encoded gene of the apicoplast-localized PfPDF and over
expressed this in E. coli. The recombinant PfPDF is catalytically active, suggesting that formylation and deformylation
process occurs in the apicoplast of the malaria parasite and
play important role in protein synthesis [31].
HsPDF is recently shown to be present in mitochondria
[16, 32]. The physiological role of HsPDF in cells is unclear.
The mitochondrial localization of HsPDF, and N-formylation
of human mitochondrial translation products for translation
initiation point at the 13 proteins encoded by the mitochondrial genome as putative substrates of HsPDF [33]. The decrease in human cell growth resulting from PDF inhibitors
actinonin and its analogues suggest that HsPDF is functional
in the mitochondria of human [34].
3. CLASSIFICATION OF PDFs
Since, Ni2+ or Co2+ substituted PDFs have activity
equivalent to that of the Fe2+, various laboratories have involved such substitutions for further overproduction and
purification of PDFs. Based on published genome sequences
and crystal structure data, three types of PDF proteins were
defined (Fig. 3). The def genes from E. coli and P. aeruginosa, which encode Type I PDFs, and those from S.
aureus and B. stearothermophilus, which encode Type II
PDFs, have been cloned and over expressed. PDFs of all

Gram-negative bacteria, some Gram-positive bacteria, and
all eukaryotes fall systematically into Type I class. The
Type II PDFs are found in Gram-positive bacteria (with
low C+G content) and mycoplasma. However, if two PDFs
occur in Gram-positive bacteria, the second is often a Type
I enzyme [35]. The third class, i.e., Type III represents
newly identified archaeal, kinetoplastids, leishmanial and
trypanosomal homologs [36]. Due to different sequences in
highly conserved motifs of Type III PDFs, in the absence
of experimental evidences, they are unlikely to function as
PDF enzyme.
4. STRUCTURE OF PDFs
Peptide deformylase was discovered 40 years ago, but as
a result of its unusually unstable activity, it was not fully
characterized until very recently when the PDF-encoding
gene, def, was cloned [25, 37]. Bacterial PDF utilizes a Fe2+
ion as the catalytic metal ion [38, 39]. However, the Fe2+ ion
in PDF is very unstable, and is rapidly and irreversibly oxidized to the Fe3+ ion through contact with atmospheric oxygen, resulting in an inactive enzyme [40]. Fortunately, it was
discovered that addition of other divalent cations in vitro,
such as Ni2+ or Co2+ resulted in better enzyme stability with
very little loss of enzyme activity [38]. Currently, crystal
PDF structures of various prokaryotes and eukaryotes have
been reported.
217
Type of PDFs
Type I
Escherichia coli, Haemophilus influenza,

Hellobacter pyroli, Legionella pneumonia,
Chlamydia trachomatis, Pseudomonas aeruginosa,
Mycobacteriam tuberculosis, Thermus thermophilus,
Deinococcus radiodurans, Treponema pallidum,
Borrella burdorferi, Prochlorococcus marinus,
Streptomyces coelicolor, Arabidopsis thaliana,
Aquifex aeolicuc, Rickettsia prowazekii,
Vibrio cholerae, Neisseria gonorrhoeae,
Clostridium acetobutylicum, Thermotoga maritima,
Plasmodium falciparum, Homo sapiens.
Type II
Type III
Leishmania major,
Trypanosoma cruzi,
Trypanosoma brucei,
Methanothermus fervidus,
Archeal PDF.
Bacillus subtilis, Mycoplasma pneunomiae,

Staphylococcus aureus,Bacillus stearotherophilus,
Staphylococcus pyrogenes, Enterococcus faecalis,
Lactococcus lactis.
Fig. (3). A phylogenetic tree for three distinct classes of PDFs.
4.1. Three-Dimensional Structure of Bacterial PDFs

Three-dimensional structure data are available for numerous PDFs. The PDFs are small monomers composed of
about 160- 200 residues. Very few variations are observed in
the lengths of their N- and C-terminal extremities. It has
been reported that the N-terminal is essential for in vitro activity whereas the C-terminal is not required for deformylase
action [41]. The conserved residues are in three short
stretches of amino acids, motifs 1 {GGAAXQ}, 2
{EGCS}, and 3 {HEDH} (where is a hydrophobic
amino acid and X is any amino acid). These three motifs
have been described as an important criterion for membership of the PDF family and for deformylase activity [42]. As
these motifs are physically close to each other and also
building the three sides of the active site crevice, the threedimensional structure of the active site of PDFs is conserved.
The amino acids cysteine of motif 2 and the two histidines of
motif 3 are involved in metal cation binding [43].
The stability of PDFs structure depends upon hydrogen
bondings between (i) side chain of the serine of motif 2 and
the glutamine side chain of motif 1 and (ii) the carboxylate of
the glutamate of motif 2 and the aspartate of motif 3 with arginine located between motifs 2 and 3 [44]. The last conserved
region residue is an asparagine, located between motifs 1 and
2. Its side-chain forms hydrogen bond with the backbone of an
amino acid located at the N-terminal of the protein. The alteration of hydrophobic and hydrophilic residues in motif 1 is
responsible for the formation of the 1 strand, along which the
peptide substrate aligns. Other less well-conserved residues
are involved in the optimization of the packing of the threedimensional structure [45]. Due to these networks of hydrogen
bondings and hydrophobic interactions, the overall structure of
PDF is very compact and solid. This makes the PDF to resist
proteolytic attacks and folding-unfolding of structure at freezing and high temperature.
The sequence similarity between Types I and IIclasses
of PDF is low, for example, the homology between the E.
coli and S. aureus proteins is only 23% [35]. Generally,

Type II PDFs are larger in size due to differences at either
the N- or C-termini, as well as internal insertions. The Cterminal of Type I PDFs (Fig. 4a) is helical, but in Type
II PDFs (Fig. 4b), the C-terminal consists of a -strand that
can fold back against the enzyme to form a -sheet. Also, Cterminal domains of Type II PDFs contain many hydrophobic amino acids, whereas Type I PDFs do not. Therefore, the C-terminal domains of Type II PDFs may not fold
into an -helix. Compared with Type I, Type II PDFs
have two sequence insertions at the N-terminal, just upstream from the 1 helix (Insertion I1) and 1 strand in motif
1 (Insertion I2). However, these differences do not significantly affect the active site regions, which are structurally
quite similar between Types I and II PDFs [42].
4.2. Three-Dimensional Structure of P. falciparum PDF
The subunit structure of PfPDF consists of a mixed -
topology, with three anti-parallel -sheets, three major helices, and one small helix near the N terminus (Fig. 4c).
The overall dimensions of a subunit are 584439 . The
enzyme structure has shown a deep pocket, which functions
as the substrate binding region. The metal ion is positioned at
the bottom of the pocket to enable the enzyme to carry out its
catalytic function. The metal ion is tetrahedrally coordinated
by three amino acid residues (Cys-155, His-196, and His200, respectively) and a water molecule.
The sequence identity between the structure of E. coli
PDF (PDB ID: 1DFF) and P. falciparum PDF (PDB ID:
1BS8) is about 33%. There are three insertions in the loop
connecting strands, 3 and 4 in the PfPDF that result in
an altered loop structure from that in the E. coli PDF enzyme. The most significant insertion is of Tyr-125, which
packs against 2 helix, forcing the latter to shift along the
helix axis toward the active site in the PfPDF enzyme. An
additional difference pertains to the last helix, comprising
amino acid residues 142-145, in the E. coli PDF enzyme.
Sangshetti et al.
Fig. (4). Comparison of PDF structures (a) E. coli (PDB ID: 1BS7); (b) S. aureus (PDBID: 2AI9); (c) P. falciparum (PBD ID: 1BS8); and (d)
H. sapiens (PBD ID: 3G5K); M1: motif 1, M2: motif 2, and M3: motif 3.
The corresponding residues form a coil in the PfPDF structure. The structural similarity is closely conserved in the
metal binding region: 44 main chain and five side chain residues (Gln-111, Cys-155, His-196, Glu-197, and His-200)
superimposed within 0.58 .
There are several important structural differences between the PDF of E. coli and P. falciparum in the substrate
binding region. First, the conserved Ile-105 in PfPDF lies
closer to the active site cavity than the equivalent Ile-44 in E.
coli PDF, making a ridge on the active site floor and decreasing the cavity volume. Specifically, the inserted residue Tyr125 in the PfPDF enzyme leans against the end of helix 2,
where the crucial Ile-105 is located, causing this helix to
move closer toward the active site. Second, the side chain of
Arg-97 in E. coli PDF acts as a lid over the active site region.
The corresponding Glu-161 in PfPDF is too short to provide
any additional interaction. Third, the Arg-97-Glu-42 pair in
E. coli PDF is replaced by the Glu-161-Lys-103 pair in
PfPDF. The change of this pair does not cause any change in
the overall electrostatic charge lining the active site cavity,
but it leads to important consequences with respect to binding of inhibitors. The fourth and last important difference,
Cys-129 in the E. coli PDF is replaced by Ile-193 in PfPDF.
This leads to decrease in volume of active site, but this difference is relatively small [31].
4.3. Three-Dimensional Structure of Human PDF
The crystal structure of human mitochondrial PDF
(HsPDF) was expressed and purified as Co2+ enzyme because this was the only metal that allowed reconstitution of
its enzymatic activity [16]. The approximately 30% sequence

similarity is observed between HsPDF and other nonmammalian PDFs, such as Gram-positive and Gram-negative
bacteria, and plants. In HsPDF (Fig. 4d), an antiparallel sheet is formed by 1 (Gly-52 to Ser-54), 2 (Val-64 to Leu67), and 3 (Arg-93 to Val-96), while a second antiparallel
-sheet is formed by 4 (Ser-99 to Leu-103), 5 (Leu-107 to
Glu-112), 6 (Ala-122 to Gly-127), 7 (Ala-128 to Leu135), and 8 (Gly-139 to Ser-147). The helices consist of 1
(Pro-32 to Arg-48), 2 (Glu71 to Glu76), 3 (Pro-79 to Arg85), and 4 (Trp-149 to Gln-162). The geometry of the metal
ion (Co2+) in HsPDF is close to tetrahedral. The Co2+ metal
ion is kept at the active site by coordination to the side chain
N atoms of His-156 and His-160, the side chain sulfur atom
of Cys-114, and a fourth unexpected ligand (PO43- ). The
topology of the metal and coordinating atoms and the metal
in HsPDF is comparable between HsPDF and other nonmammalian PDFs.
The HsPDF shares the hairpin loop anchoring points
that shape the entrance to the active site in the PDF family.
However, the conformation of the C-terminus in HsPDF, in
combination with the presence of the 2/3 helical loop creates a characteristic entrance to its active site compared to
non-mammalian PDFs. The sequence identity between the
structure of HsPDF and E. coli PDF is low (~21%). The topology of amino acid residues involved in the reaction
mechanism and metal coordination is conserved; this suggests that the mechanism of catalysis of HsPDF is also conserved. The substrate binding S1 pocket is conserved in
HsPDF, but lacking the S2and S3 pockets as observed in
other PDFs. Despite HsPDF lacking true S2and S3 substrate

binding pockets, the residue surrounding the S2and S3
pockets such as Arg-48, Met-87, Arg-85, Pro-111, Glu-115,
Leu-121, and Trp-149, which create a hydrophobic depression, could contribute to binding specificity.
The HsPDF enzyme shares only 28% amino acid sequence identity with malarial enzyme (PfPDF). The difference in the substrate binding pocket between HsPDF and
PfPDF include: (i) Arg-107 in HsPDF verses Lys-103 in
PfPDF, (ii) Val-109 in HsPDF verses Ile-105 in PfPDF,
(iii) Leu-179 in HsPDF verses Glu-161 in PfPDF, and (iv)
Pro-169 in HsPDF verses Ile-152 in PfPDF [30]. The
amino acid sequences of PfPDF, EcPDF and HsPDF are
shown in (Fig. 5).
219
in size and shape among PDFs from various Gram-positive

and Gram-negative organisms. The S1 pocket is formed by
Ile-44, Ile-86, Glu-88, Leu-125, Ile-128, Cys-129, and His132. The only non-conservative amino acid residue in this
region lies on the border between the S1 and S3 pockets. The
residues are Leu-125 in E. coli, Leu-125 in H. influenza,
Leu-127 in P. aeruginosa, Leu-146 in B. stearothermophilus, Tyr-166 in S. pneumoniae, Tyr-147 in S. aureus, and
Tyr-122 in T. marimata. A good enzyme inhibition can be
obtained with inhibitors that bind only to the metal and into
the S1 pocket in both Gram-positive and Gram-negative
PDFs [46, 47].
4.4.2. S2 Pocket
The active site of PDF proteins contains three substratebinding pockets along with the metal binding site (Fig. 6).
These pockets are referred to as S1, S2 and S3 pockets and
corresponding positions on substrate or inhibitors are referred to as P1, P2 and P3.
The S2 pocket is an open tunnel-like space pointing out

into solvent. The amino acid residues lining the S2 pocket
differ in different species, but overall chemical nature remains the same for all PDFs [35]. This region is able to accommodate a large variety of side chains presented by the
various formylated substrates to be processed by the PDF
proteins [48].
4.4.1. S1 Pocket
4.4.3. S3 Pocket
The S1 pocket of PDF is mostly hydrophobic pocket and

conserved among all of the bacterial PDF [35]. This pocket
is the binding site for the methionine side chain, which is
required to remove the formyl group from the Nformylmethionine peptide. This pocket remains very similar
In contrast, the S3 pocket of PDFs is the least conserved

region and showed greater variation among the species that
alter both the shape and chemical nature of the pocket [35].
Similar to S2 pocket, this region is also solvent exposed and
more of a surface depression [46].
4.4. Substrate-Binding Pockets
Fig. (5). An alignment of amino acid sequences in P. falciparum (PfPDF), E. coli (EcPDF), and H. sapiens (HsPDF) [31].
Sangshetti et al.
preferably deformylated by E. coli PDF. The study revealed

that the optimal residue at P1 (Fig. 6) was methionine with
glycine and aromatic amines (histidines, phenylalanine, and
tyrosine) following at a distant second and third. No selectivity was observed at P2 residues as all amino acids were selected at similar frequencies except for glycine, aspartate,
and glutamate, which were not selected by the enzyme as
PDF substrate. The P3 residue showed a strong preferences
for an aromatic residue as over 80% of the selected beads
either had tyrosine, phenylalanine or histidine at this position.
Fig. (6). Schematic representation of the PDF active site.
4.5. Metal-Binding Site

PDFs are metalloprotease enzyme. The crystal structures
of PDF with Fe2+, Ni2+, Co2+, and Zn2+ have been solved and
no significant structural differences are observed among the
various metal forms. Metal ion in the active site of PDF is
tetrahedrally ligated and bound to the two histidines from the
HEDH motif, as well to a cysteine and a water molecule
(Fig. 5) [26]. The four ligands are N atom in His-132, His136 of the highly conserved HEDH sequence, S atom of
Cys-90 in the EGCS sequence and O atom in water molecule. All of these ligands are aligned precisely within an extended H network involving most highly conserved residues
as:
1) His-132 is held in position by hydrogen bonding with
Glu-88, which in turn forms hydrogen bonding with Arg102. The Arg-102 also forms hydrogen bonding with
highly conserved Asp-135.
2) His-136 is held in place by two hydrogen bonds with a
water molecule which in turn forms hydrogen bond with
the backbone of Leu-13.
3) The ligated water molecule forms two hydrogen bonds
with highly conserved Glu-133 and one hydrogen bond
with another highly conserved residue Gln-50. The Gln50 forms hydrogen bonds to conserved Ser-92, Ala-47,
and water molecule. Ser-92 forms hydrogen bond with
the backbone of Leu-6 [44].
5. DISCOVERY OF PDF INHIBITORS
A rational, mechanism-based approach has been successfully used to design the several therapeutically important
metalloprotease inhibitors. The metalloproteases such as
angiotensin converting enzyme (ACE) and matrix metalloproteases (MMPs) are among the best studied of enzyme
class and they are excellent precedents for the mechanismbased design of their inhibitors [49]. The fact that PDF is
also metalloprotease enzyme, gives it an added attractiveness
as a target for drug discovery, since it permits the rational
design of inhibitors. So similar strategy like, ACE inhibitors
and MMP inhibitors can be adopted to discover therapeutically important PDF inhibitors.
The successful development of E. coli F-PDF [34] led
the several groups to investigate and design the substrate
analogues as PDF inhibitors. Hu and co-workers [48] prepared a combinatorial library of resin-bound formylated
tetrapeptide substrates and evaluated which sequentially and
Actinonin is the first reported naturally occurring PDF

inhibitors obtained from Streptomyces species [50]. Although actinonin is too weak as PDF inhibitor due to its poor
bioavailability, it did form the framework for the synthesis,
purification, and evaluation of more potent PDF inhibitors.
Based on the mechanistic and structural information, together with understanding of the general principles of inhibiting metalloproteases, a generic PDF inhibitor structure was
proposed [23] (Fig. 7). In this structure, (i) X represents a
metal cation-chelator that will be responsible for providing
binding energy, (ii) the n-butyl group is used to mimic the
methionine side chain of the substrate at P1, and (iii) side
chain at P2 and P3 regions of the inhibitor can provide additional binding energy, selectivity, and favorable pharmacokinetic and toxicities properties. All PDF inhibitors reported to date contain a functional moiety that can chelate
the metal ion of the enzyme. Others, while they may not fit
the generic inhibitor structure directly, can still be viewed as
structures with characteristics of metal cation-chelator [11].
P1
O
H
N
X
O
N
H
P3
P2
Fig. (7). Proposed general structure for PDF inhibitors.
6. PDF INHIBITORS
The PDF inhibitors demonstrate potent activity against a
wide spectrum of bacterial species, including but not limited
to, E. coli, B. sublitis, S. aureus, S. pneumoniae, S. pyogenes,
S. agalactiae, V. streptococci, H. influenzae, M. catarrhalis,
M. pneumoniae, C. pneumoniae, B. fragilis, M. tuberculosis,
H. pylori, P. aerogenosa, Enterococcus spp., Fusobacterium
spp., and anaerobes, such as Clostridium spp. Some reports
suggest that the in vitro growth of P. falciparum could be
inhibited by PDF inhibitors, thus further supporting the potential use of PDF inhibitors as anti-parasitic agents. Some
PDF inhibitors have also been reported to inhibit tumor
growth, both in vitro and in vivo. Using rational design, random screening or the screening of rationally designed, focused chelator-based libraries, many structural different
classes of PDF inhibitors have been identified. The classification of PDF inhibitors are presented in (Fig. 8).
6.1. PDF Inhibitor as Antibacterial Agents
The PDF inhibitors with antibacterial activity inhibit the
enzyme activity very effectively. The PDF inhibitors may
also work via stimulation of the innate immune system.
221
Fig. (8). Classification of PDF inhibitors.
In this system, activation of formyl peptide receptors (FPR)

mediates phagocyte (neutrophil) migration and release of
free radicals and other antibacterial substances from phagocytes. Theoretically, PDF inhibitors should enhance this response and, hence, innate immunity. This has been demonstrated with actinonin in animal models and results showed
that actinonin enhances the production and secretion of neutrophil-activating peptides that work via FPR [51]. The existence of HsPDF undoubtedly raises the issue of potential
mechanism-based toxicities. However, the lead PDF inhibitors exhibit activity against HsPDF enzyme only at extremely high concentrations and have excellent safety profiles in the preclinical development [52]. In the past few
years, several classes of PDF inhibitor as antibacterial agents
have been reported.
6.1.1. Peptidic Inhibitor as Antibacterial Agents
6.1.1.1. Thiol Derivatives
Various metal-binding groups such as thiols, carboxylates, hydroxamates, and phosphonates have been used to
replace the scissible bond of substrates processed by thermolysin. Yaoming et al. explored thiol derivatives for their ability to form tight-binding complexes with ferrous and nickel
ions [53]. The synthesized compounds exhibited competitive
inhibition against E. coli PDF enzyme. The structure-activity
relationship studies revealed that replacement of anthracene
moiety with naphthalene ring had improved the potency by
3-5 folds. Further reduction of size aromatic ring to just one
ring led to slightly decrease in the inhibitory potency. Therefore, an aromatic amine containing two rings appeared to be
best accommodated by the PDF active site. The most potent
compound (1) has inhibition constant (KI) 0.015 0.002 M
against E. coli PDF.
NH
HN
NH2
O
SH
HN
(1) O
The same group has also designed and synthesized a series of peptide thiols that act as potent, reversible inhibitors
of purified recombinant PDF from E. coli and B. sabtilis
[54]. The most potent inhibitor (2) has a KI value of 0.011
M toward the B. subtilis Co-PDF enzyme. These inhibitors
showed antibacterial activity against both Gram-positive and
Gram-negative bacteria, with MIC (Minimum inhibitory
concentration) value as low as 2 g/mL. These PDF inhibitors had induced bacterial cell lysis and showed bactericidal
activity towards all four bacterial strains that have been
tested, B. subtilis, S. epidermidis, E. faecalis, and E. coli.
H
N
HS
O
NO2
O
N
H
(2)
6.1.1.2. H-Phosphonate Derivatives

Similarly, Yun-Jin et al. explored the feasibility of using
an H-phosphonate as metal-binding group to inhibit the PDF
activity [55]. The structure of H-phosphonate compounds
revealed that H-phosphonate group could potentially resemble the tetrahedral intermediate or the transition states for the
formation and/ or breakdown of the intermediate and, therefore, act as a deformylase inhibitor. The inhibitor (3) was not
highly potent (KI = 37 M versus E. coli Fe-PDF and KI = 76
M versus E. coli Zn-PDF).
O
O
O
P
H
OH
Sangshetti et al.
N-formyl-N-hydroxylamine exhibit appreciable antibacterial

activity. Most PDF inhibitors identified to date share a common structural feature of a chelator + peptidomimetic scaffold [20]. Researchers of British Biotech reported the Nformyl hydroxylamine containing compound, BB-3497 (6)
as an effective inhibitor (IC50= 0.007 M) of the E. coli NiPDF enzyme, exhibiting potent antibacterial activity both in
vitro and in vivo [58].
H
N
N
H
OH
N
NO2
(3)
6.1.1.3. Aldehyde Derivatives

Researchers at Merck Research Laboratory investigated a
small set of peptide aldehyde inhibitors, postulating that the
aldehyde might bind to the metal centre in the form of a hydrate, thus serving as a transition state mimetic [56]. The
most potent inhibitor was calpeptin (4) and showed good
inhibitory effect against the zinc-containing metalloenzymes,
E. coli and B. subtilis PDF with KI values of 26 and 55.6
M, respectively. Cobalt-substituted E. coli and B. sabtilis
PDFs were also inhibited by these aldehydes with KI values
for calpeptin of 9.5 and 12.4 M, respectively. Calpeptin has
a similar potency and mechanism of inhibition with PDFs
from both Gram-negative (E. coli) and Gram-positive (B.
subtilis) bacterial sources. This gives added support to the
proposal that a single PDF inhibitor might have broadspectrum activity.
O
O
N
H
(4)
OH
N
OH
H
N
H
N
O
Actinonin
(5)
O
N
O
BB-3497
(6)
6.1.2.2. P2-Pyrrolidine Containing Inhibitors

Using a combination of iterative parallel synthesis and
traditional medicinal chemistry, researchers at Versicor and
Novartis have identified a new potent class of PDF inhibitors
with N-alkyl urea at P1 site [59]. These compounds have
shown MICs of 4 g/mL against Gram-positive and Gramnegative pathogens, including S. aureus, S. pneumoniae, and
H. influenza. The IC50 values for these compounds for E. coli
Ni-PDF and S. pneumoniae Zn-PDF enzymes were 0.1 M.
In addition, these compounds were very selective for PDF,
with IC50 values >200 M for matrilysin (MMP-7). Molecular modeling information indicated that the urea compounds
adopt a binding position similar to that for succinate hydroxymates. The most potent compound (VRC4307) (7) has
displayed in vivo efficacy in a mouse protection assay, with
50% protective dose of 17.9 mg/kg.
H
N
O
O
Calpeptin
O
HO
6.1.2. Pseudopeptidic Inhibitors as Antibacterial Agents

6.1.2.1. Hydroxamic Acid or N-formyl-N-hydroxylamine
Derivatives
Actinonin (5) is a peptidic hydroxamic acid has been
known as moderate antibacterial agents. Despite minor differences in the PDF active sites and secondary structures,
actinonin adopts a similar binding conformation in all of the
PDF enzymes for which co-crystallization data are available.
The conserved residues involved in binding interactions with
actinonin are concentrated in the S1 pocket, related to or
needed for metal coordination, or involved in H-bonding to
the amide bonds [34]. It has never been developed as therapeutic agent due to lack of in vivo efficacy in animal models
of infection, due to its known instability. It also lacks the
selectivity against human secondary targets, as it binds other
classes of metalloproteases [57].
However, actinonin as a potent inhibitor of PDF was a
key discovery in the development of newer PDF inhibitors
with superior enzyme binding through a metal-chelator. Although compounds with many different chelators can inhibit
the enzyme, only compounds containing hydroxamic acid or
N
H
O
O
VRC4307
(7)
S
N
H
Researchers at Vicuron (formerly Versicor) and Novartis

further investigated the analogues of 2-R-butyl succinic acid
and explored the structure-activity relationship (SAR) of
various chelator groups, -substituents, P2 and P3 substituent
in order to achieve optimal antibacterial activity with minimal toxicity liability [60]. In vitro study indicated that hydroxamate group provided that best enzyme inhibition and
antibacterial activity among various chelators tested. At P2
position, cyclic 4-6 member amino acids were incorporated
and found that proline group could be preferred. The structure-activity relationship of P3 position revealed that a proper
hydrophilic and hydrophobic would be required for maximal
antibacterial activities with reduced toxicity. Pyrrolidine at
P3 position showed the best combination of in vitro potency,
cytotoxicity and selectivity. The most potent compound (8)
has MIC values 1-2, 0.25-1, and 0.25-1g/mL for S. pneumoniae, S. aureus, and H. influenza, respectively, and IC50
value 0.02 M for E. coli Ni-PDF.
O
HO
N
H
O
(8)
N
H
Scientists at Novartis also designed and synthesized the

highly potent PDF inhibitor of M. tuberculosis [61]. In this
study, they have introduced the benzimidazoles and benzoxazoles moieties in peptidomimetic chain to reduce the peptidic character. The two most potent compounds, one from
each series, (9) and (10) showed IC50 value 0.01 and 0.013
M, respectively, for M. tuberculosis Ni-PDF. These compounds have also shown excellent activity against single and
multi-drug resistant M. tuberculosis strains. The compound
(9) showed MIC values of 0.1, 0.03, 0.2, 0.125, 0.25, and
0.03 g/mL and compound (10) 0.15, 0.06, 0.5, 0.6, 0.25,
and 0.06 g/mL against M. tuberculosis strain H37Rv, isoniazid single-drug resistant strain, streptomycin-resistant
strain, rifampicin-resistant strain, pyrazinamide-resistant
strain, and Beijing W multi-drug-resistant strain, respectively.
O
OH HN
N
O
OH
O
(10)
(9)
In search of potent antibacterial agents against Grampositive pathogens, Zhenyu et al. have synthesized novel
(2S)-N-(substitutedphenyl)-1-[2R)-2-[(formylhyroxyamino)
methyl]-1-oxohexyl]-2-pyrrolidinecarboxamide analogues of
PDF inhibitor [62]. Modification at P3 position in PDF inhibitors with hydrophobic group have been shown to an improvement of both enzymatic and whole-cell activities. One
of the most important features of the fluoroquinolone antibacterials is the presence of a nitrogen-containing aliphatic
heterocycles at position 7 in the quinolone scaffold, with the
effect of improving antibacterial activity and/ or pharmacokinetic properties. Based on these, they investigated the
PDF inhibitors with the nitrogen-containing aliphatic heterocycles at the P3 position. The most potent compound (11) has
shown MIC values 0.139, 0.049, 0.195, 0.049, and 0.39
g/mL against S. aureus, S. pneumoniae, S. albus, S. enteridis, and S. non-hemolyticus, respectively.
HO
CHO
N
N
O
223
[63]. In this study, they have replaced the n-butyl with cyclopentyl methyl group at P1 position and synthesized the
three series as imide, acylcarbamate and Nhyrdoxyformamide derivatives. Among the three series, Nhyrdoxyformamide derivatives have shown better potency in
the enzyme assay as well as antibacterial activities, particularly against S. pneumoniae. The most potent compound (12)
has IC50 values 0.0009, 0.0003, and 0.0018 M (PDF inhibitory activity) and MIC values 0.125, 0.125, and 0.5 g/mL
against S. aureus, S. pneumoniae, and H. influenza, respectively.
N
HO
O
CHO O
N
H
NH
(12)
6.1.2.3. P2-Dihropyrrole Containing Inhibitors

Wei et al. have reported 2,5-dihyropyrrole formyl hyrdoxyamine derivatives as novel and potent PDF inhibitor and
screened against both Gram-positive and Gram-negative
pathogens [64]. The replacement of pyrrolidine with 2,5dihyropyrrole group at the P2 position and introduction of
heterocyclic amine at P3 position in peptidomimetic chain
resulted in good to excellent antibacterial activity. The most
potent compound (13), which contains thiadiazolyl functionality, exhibited MIC values 0.0625 to 0.25 g/mL against
Gram-positive bacterial strains including S. aureus, methicillin-susceptible S. aureus (MSSA), methicillin-resistant S.
aureus (MRSA), and S. epidermis and 16 to 32 g/mL
against Gram-negative bacterial strains including E. coli 1
(ATCC25922) and E. coli 2 (ATCC35218).
H
HO
O
N
N
O
N
O
H
(13)
N
CF3
S
6.1.2.4. P2-Methylenepyrrolidine Containing Inhibitors

In search of new PDF inhibitors Wei et al. have reported
3-methylenepyrrolidine formyl hydroxyamino derivatives
and screened in vitro antibacterial activities against Grampositive pathogens [65]. The most potent compound (14),
which contains thiazoly functionality at P3 position and cyclopentylmethyl group at P1, exhibited MIC values 0.0625 to
0.5 g/mL against Gram-positive bacterial strains including
S. aureus, methicillin-susceptible S. aureus, methicillinresistant S. aureus, and S. epidermis.
6.1.2.5. P2-Oxazolidine Containing Inhibitors
O
(11)
N
H
Scientists at GlaxoSmithKline have reported acylprolinamide derivatives as potent, broad-spectrum PDF inhibitors
Oxazolidine moiety is an important building block for

many biologically active agents. It is called pseudoproline
and mimics the proline skeleton of pseudopeptidic inhibitors
[66-68]. Linliang et al. have reported the substitution of oxazolidine moiety at P2 position in peptidomimetic chain and
Sangshetti et al.
synthesized a series of (2S)-N-substituted-1-[(formyhydroxyamino) methyl]-1-oxohexyl]-2-oxazolidinecarboxamide derivatives as antibacterial agents [69]. These compounds have
shown significantly better antibacterial activity against
Gram-positive bacteria than Gram-negative bacteria. The
most
potent
compound
(15)
with
3-chloro-4morpholinylphenyl substitution at P3-position has MIC values 0.39, 0.098 and 0.39 g/mL against Gram-positive organisms including S. aureus, S. pneumoniae, and S. albus,
respectively, and 6.25 g/mL against both Gram-negative
bacteria including S. boydii and S. flexneri.
O
HO
H
N
HO
N
O
O
(14)
N
O
Cl
O
N
H
N
H
(15)
6.1.2.6. P2-Azaamino Containing Inhibitors

Bioisosteric replacement of amino acids with azaamino
acids is a peptidomimetic strategy which has been applied to
a number of protease inhibitors [70]. Also, azaamino acids
are more stable, particularly to hydrolytic cleavage by proteolytic enzymes. Researchers at Vernalis have investigated
the N-formyl hydroxylamines containing azaproline and
azapicolinic acid as E. coli Ni-PDF enzyme inhibitor [71].
The five-membered furan containing compounds at P3 position provided the best potent compounds with IC50 value
ranging from 0.005-0.03 M. The most potent compound
(16) has IC50 value 0.005 M for E. coli Ni-PDF enzyme and
MIC values 0.5-2 g/mL against S. pneumoniae (Grampositive bacteria) and <0.125-0.25, and <0.125 g/mL
against H. influenza, and M. catarrhalis, respectively (Gramnegative bacteria).
HO
(17)
N
O
(16)
N
H
(18)
OH
OH
N
(19)
6.1.3.2. Bicyclic Hydroxamic Acid Derivatives

Scientists at Hoffmann-La Roche Ltd. have developed
and synthesized structurally related bicyclic hydroxamic acid
derivative as potent and selective new E. coli PDF inhibitors
[75]. They synthesized two series of related hydroxamic acid
analogues, quinazoline hydroxyl-acetamides, and thiadiazine
hydroxyl-acetamides. The two most potent compounds, one
from each series, (20) and (21) showed IC50 value 0.31 and
0.12 M, respectively. However, these compounds showed
weak antibacterial activity.
H
N
N
N
H
O
(20)
N
O
S
O
N
O
H (21)
OH
H
N
OH
The group at Novartis has identified and synthesized new

thiazepine derivative as very potent inhibitors of S. aureus
Ni-PDF with an IC50 in the low nanomolar range [76]. Many
of the synthesized compounds proved to be excellent S.
aureus Ni-PDF inhibitors, but lacked the antibacterial activity. In order to improve antibacterial activity, they prepared
the corresponding sulfone and carbon analogues. These analogues showed lower potency than thiazepine series. Further
study revealed that these molecules are unable to penetrate
the outer cell membrane of E. coli and may bind to the cell
membrane of S. aureus. The most potent compound (22) has
shown IC50 value <0.005 M.
H
N
N
O
H (22)
O
N
S
HO
OH
OH
6.1.3. Non-Peptidic Inhibitors as Antibacterial Agents

6.1.3.1. Thyropropic Acid Derivatives
Researchers at Pfizer Global Research reported some thyropropic acid derivative as a novel, non-peptidic inhibitors of
E. coli PDF [72]. SAR study demonstrated that the carboxylate group is required for activity as ester and amide analogues are less potent. The best compound (17) has IC50
value 0.94 0.05 M. This compound inhibited E. coli PDF
similar to actinonin, but lacked antibacterial activity. These
compounds were the first non-peptidic inhibitors disclosed
and used as template to discover better PDF inhibitors.
GlaxoSmithKline has got a patent for hydroxamic acid (18)
and N-formyl-N-hydroxylamine (19) analogues of a thyropropic acid core as PDF inhibitors [73, 74].
6.1.3.3. -Sulfonyl- and -sulfinylhyrdoxamic Acid Derivatives

Scientists at Hoffman-La Roche Ltd. have reported sulfonyl- and -sulfinylhyrdoxamic acid derivatives as new
class of potent PDF inhibitor [77]. In this, they replaced amide group with sulfonyl (23) and sulfinyl (24) group and
evaluated for PDF enzyme activity. The sulfonyl-containing
compounds generally demonstrated better enzyme inhibitory
activity than the sulfinyl compounds. This trend was reversed with respect to antibacterial activity in spite of their
weaker enzymatic activity. However, the antibacterial activity against Gram-positive bacteria was poor.
6.1.3.4. Biaryl Acid Derivatives
The biaryl acid analogues were developed by Merck Research Laboratories and evaluated as PDF inhibitor against
E. coli PDF [78]. All the inhibitors contain acidic pharmacophore, including tetrazole, acyl sulphonamide and carboxylate. Structure-activity relationship studies of biaryl acid
analogues revealed that substitution at the head group, biaryl
group, and the nature of acidic group all contributed to the
inhibitory activity of the these compounds against PDF.
Tetrazole and acyl sulphonamide analogues appeared to provide the best potency. The acidic group of these compounds
may bind to the metal ion and instead interact with an amino
acid residue within PDF active site much like the binding of
the angiotensin II receptor. The most potent compounds, one
from each acidic pharmacophoric series (25), (26), and (27)
showed IC50 value 3.9, 10, and 22.8 M, respectively. The
antibacterial activity of these compounds was not reported.
O
S
H
N
O
O
S
OH
H
N
N
O
N
N
OH
N N
N
NH
N
N
Cl
(26)
(25)
N
HN
O
O
O
S
OH
NH
S
N
(30)
6.1.3.7. Isoxazole Derivatives
(24)
oxidation of sulfur of benzthiazole ring to sulfone resulted in

complete loss of PDF inhibitory activity. SAR studies revealed that increase in the length of N-alkyl chain enhanced
the PDF inhibitory activity. The compounds showed antibacterial activity against S. aureus and P. aerogenosa, but they
were inactive against E. coli. The most potent compound
(30) has IC50 value 1.04 M for PDF enzyme inhibition and
MIC value 10 g/mL against S. aureus.
OH
(23)
225
Fieulaine et al. have designed and developed a series of

isoxazole-3-hydroxamic acid derivatives as potential inhibitor of E. coli and S. aureus PDF enzymes [82]. Molecular
modeling studies predict that the aryl substituent of isoxazole
binds into S1 pocket and that the oxygen atom of the isoxazole is involved in an H-bonding interaction with Ile-44 in E.
coli PDF, similar to the P1 carbonyl of actinonin (5). The
compounds showed better enzyme inhibitory activity for S.
aureus as compared to E. coli. The oxidation of thioether
derivatives to sulfoxide and sulfone has resulted in slightly
improved PDF enzyme inhibitory activity with decrease in
IC50 value 1.5-3 times than the corresponding un-oxidized
compounds. The most potent compound (31) has IC50 value
3.4 M for E. coli PDF enzyme and the compound (32) has
0.8 M for S. aureus PDF enzyme. The poor antibacterial
activity of these compounds may be due to poor penetration
of the bacterial cell wall.
(27)
O
N
6.1.3.5. Benzamide and Aryl Ether Derivatives
The group at GlaxoSmithKline has published a patent

application covering the series of aryl ether (28) and benzamide (29) derivative as novel PDF inhibitors [79, 80].
These inhibitors were designed to explore the feasibility of
preparing small molecular weight, non-peptidic compounds
that would bind only into well conserved S1 pocket. The
reported compounds have shown potent enzyme inhibitory
activity (<0.1 M). The benzamide series has shown excellent oral bioavailability (100%) in a H. influenza respiratory
tract infected rat model (in vivo model).
Cl
Cl
O
O
H
N
H
(28)
OH
(29)
O
N
OH
6.1.3.6. Benzothiazole Derivatives

Wataru et al. have reported a novel series of benzothiazole derivatives as potent non-peptidic PDF inhibitor [81].
The newly synthesized compounds were evaluated for their
in vitro inhibitory effect on E. coli Ni-PDF enzyme and exhibited micromolar order enzyme inhibitory activity. The
N
H
OH
O
HO
S
(31)
N
H
N O
Cl
(32)
6.1.3.8. Macrocyclic Derivatives

A macrocyclic PDF inhibitors comprise of peptide mimetic chain having three residues, P1, P2, and P3, wherein P2
connects with P1 and P3, wherein P1 and P3 each have a side
chain, and wherein the side chains on P1 and P3 are crosslinked to complete the cycle. Since most of the PDF inhibitors
have significant peptide characteristics, there are some concerns about their selectivity (e.g., inhibition of matrix metalloproteases) and in vivo stability (e.g., proteolysis of peptide
bond). The best approach to improve both selectivity and stability of PDF inhibitors is to form cyclic peptides or dipeptides
[59]. Xubu et al. have designed and reported the macrocyclic
PDF inhibitor of E. coli Co-PDF enzyme [83]. The macrocycle containing N-formylhydroxylamine side chain as metalchelating was synthesized from a diene precursor via olefin
metathesis using Grubbs catalyst. The cyclic inhibitor (33)
showed potent inhibitory activity toward E. coli PDF enzyme
(KI= 0.00067 M) and antibacterial activity against both
Gram-positive and Gram-negative bacteria (MIC= 0.7-12
g/mL). The group has further studied the structure-activity

relationship on the size of the macrocycle and found that 1517-membered macrocycles are optimal for binding to the PDF
active site. Unlike the acyclic compounds, which are simple
competitive inhibitors, the cyclic compounds all act as slowbinding inhibitors. As compared to their acyclic counterparts,
the cyclic inhibitors displayed 20-50-fold higher potency
against the PDF active site, improved selectivity toward PDF,
and improved the metabolic stability in rat plasma. Some of
the macrocyclic inhibitors had potent, broad spectrum antibacterial activity against clinically significant Gram-positive and
Gram-negative pathogens.
O
N
H
N
OH
O
HN
Sangshetti et al.
metal-binding group and (ii) the P1 group, which binds the

S1 pocket of PDF [86]. The increase in entropy due to the
binding of either of these low-affinity binding groups results
in the molecule being a potent PDF inhibitor, with inhibition
constants in the nanomolar range. The S1 pocket of bacterial
PDFs of both types (I and II), accepts n-butyl, n-pentyl, nhexyl, n-phenyl, and other cyclic side chains with low levels
of selectivity. The HsPDF has a modified S1 pocket that
cannot tolerate bulky chains such as phenyl chains [87, 88].
Based on these facts, Adrien et al. have discovered and reported indole (bulky and cyclic ring) derivatives as a new
class of potent and selective bacterial PDF inhibitor [89].
They developed a dual-screening strategy for selecting
highly effective compounds with low inhibition effect
against HsPDF. The most potent compound (36) has IC50
values 360 M for HsPDF enzyme and 0.013 M for E. coli
PDF enzyme. This compound has also shown potent broad
spectrum antibacterial activity with MIC value 6 g/mL
against E. coli and 3.1 g/mL against B. subtilis bacterium.
(33)
Gang et al. have reported a novel class of macrocyclic

peptidyl hydroxamates from commercially available 5hexenoic acid and evaluated as E. coli Co-PDF inhibitors
[84]. In this work, they have replaced the Nformylhydroxylamine moiety with another metal chelating
group, the synthetically more accessible hydroxamate. The
most potent compound (34) exhibited tight, slow-binding
inhibition of E. coli PDF (KI = 0.0044 M) and had potent
antibacterial activity against Gram-positive bacterium B.
subtilis (MIC = 2-4 g/mL).
O
HO
H
N
N
H
O
O
HN
(34)
N
OH
N
H
N
HN
OCH3
(35)
The same group has further studied the compound (36) to

investigate the effect of substituent at position 5 and optimize position 1 to improve the both potency and antibacterial
activity [90]. For this purpose, they synthesized the morphomimetic series, termed reverse indole. The PDF inhibitory data of indole derivatives revealed the selectivity for
bacterial PDF enzyme. The structure-activity relationship has
suggested that bromine is the best group at position 5 and
cannot be replaced by bulkier substituents. The substitution
of N-benzyl group at position 1 has resulted in most potent
compound with improved the potency relative to compound
(37). This potent compound (37) has IC50 value 0.008 0.001
M for E. coli PDF enzyme and MIC value 1-2 g/mL
against B. subtilis.
6.1.3.9. Benzimidazole Derivatives

Ling et al. have reported benzimidazole derivative as
new class of PDF inhibitors [85]. The molecular docking
study of synthesized compounds against the crystallographic
structure of E. coli Ni-PDF enzyme revealed that N atom of
benzimidazole ring formed the hydrogen bond with amine
hydrogen of Gly-89. The functional group HCO-NOH group
chelated the Ni2+ ion and formed the hydrogen bonds with
Gln-50, Leu-91, and Glu-133. All the synthesized compounds were screened for in vitro antibacterial activities
against S. aureus and K. pneumoniae. All the target compounds exhibited weak inhibitory activity against K. pneumoniae. The compounds possessing electron-withdrawing
groups on benzimidazole ring have shown increased antibacterial activity against S. aureus. The most potent compound
(35) has MIC value < 1 g/mL against S. aureus.
6.1.3.10. Indole Derivatives
The binding affinity of PDF inhibitors depends essentially on the additive effects of two chemical groups: (i) a
O
N
N OH
H
Br
H
N OH
Br
N
H (36)
(37)
6.1.3.11. Dithiazole Derivatives

Alexander et al. have unexpectedly discovered that the
solution of 2-amino-5-mercapto-1,3,4-thiadiazole (AMT)
(38) in dimethylformamide solvent (but not in any other solvents) served as a slow-binding inhibitor of E. coli Ni-PDF
inhibitor upon aging [91]. The DMF-mediated activation
involves the dimerization of two 2-amino-5-mercapto-1,3,4thiadiazole molecules via the dithiol linkage forming bisAMT (39), which serves as a slow-binding inhibitor of enzyme. The magnitudes of KI for AMT and bis-AMT as being
equal to 129 and 3.7 M, respectively, it is significant that
the slow-binding step enhances the apparent binding affinity
of AMT for the enzyme by about 30 fold. The molecular

modeling study revealed that metal ion of enzyme coordinated with the 2-amino group of bis-AMT as well as the adjacent ring nitrogen of the thiadiazole ring at the distance of
2.55 and 2.81 , respectively.
227
tive inhibitor against HpPDF, with an IC50 value of 4.02

M.
Furthermore, absorption spectra and crystal structural characterization revealed that CAPE did not chelate HpPDF and
did not disrupt the metal-dependent catalysis.
O
H2
N
N N
SH
S
H2
N
N N
(38)
N N
HO
NH2
CAPE
(44)
HO
(39)
6.1.4. Naturally Occurring PDF Inhibitor as Antibacterial

Agents
Actinonin (5) was the first reported as naturally occurring
PDF inhibitor with a metal ion-binding hydroxamate moiety
and a tripeptide binding domain. Yoo et al. have reported a
new 24-membered ring lactone compound named macrolactin N (40) as potent PDF inhibitor [92]. This compound was
isolated from a culture broth of B. sabtilis. The compound
has IC50 value of 7.5
M for S. aureus PDF and inhibited
bacterial growth against E. coli with a MIC of 100
g/mL,
while inhibiting weaker bacterial growth against S. aureus
and B. subtilis with a MIC50 of 100
g/mL, respectively.
Fumimycin (41) was isolated from the fermentation broth
of A. fumisynnematus F746 [93, 94]. It possess a skeleton
with a six-membered ring fused with the similar fivemembered lactone and an ,-disubstituted amino acid moiety linked to a fumaric acid residue. Besides exhibiting antibacterial activity against S. aureus, MRSA (methicillin resistant S. aureus) and QRSA (quinolone resistant S. aureus),
the compound has promising inhibitory activity towards S.
aureus PDF with an IC50 of 4.1
M. The same group has also
isolated a hydroxylated 1,3-dihydroisobenzofuran derivatives
FR198248 (42) and FR202306 (43) as potent PDF inhibitor
from A. flavipes. The compounds (42) and (43) inhibited S.
aureus PDF with IC50 values of 3.6 and 2.5
M, respectively,
and also showed antibacterial activity with an MIC value of
25
g/mL against S. aureus [95].
6.2. PDF Inhibitor as Antimalarial Agents

The finding of PDF in eukaryotic parasites such as
PfPDF suggests that it might be a good target for new antimalarial drugs. Several reports suggest that the in vitro
growth of P. falciparum could be inhibited by PDF inhibitors, thus further supporting the potential use of PDF inhibitors as antimalarial agents. Actinonin (5) inhibits the growth
of P. falciparum with an IC50 of 3
M. However, actinonin
has no effect against malaria in vivo in a rodent model of
malaria [30, 97, 98].
Abhinav et al. [31] have studied the crystal structure of
PfPDF (PDBID: 1JYM) and suggested regarding the design
of improved inhibitors of PfPDF. They have suggested that
replacing the lysyl side chain of inhibitor (45) by a negative
charged side chain of similar length is likely to remove the
repulsive interactions between inhibitor (45) and the PfPDF
enzyme. The same research group [99] has further improved
crystal structutre of PfPDF (PDBID: 1RL4). They added a
synthesized potent PfPDF inhibitor (46) that had an IC50 of
0.13 M against PfPDF to crystallization screens, in order to
structurally characterize the interaction between PfPDF and
inhibitor. The P1, P2 and P3 components of inhibitor (46) have
corresponded very well with the destiny PfPDF enzyme.
HS
OH
OH
NO2
H
N
N
H
O
O
O
HN
O
CH3
(45)
O
HO
HO
Macrolectin N
(40)
Fumimycin
(41)
O
HO
HO
OH
OH
FR198248
(42)
H
O
HO
HO
NH2
NH2
OCH3
OH
FR202306
(43)
Recently, Kunqiang et al. have reported caffeic acid

phenethyl ester (CAPE) (44), an active component of propolis, as inhibitor of H. pylori PDF (HpPDF) [96]. Propolis, a
natural antibiotic from honey bees, is reported to have an in
vitro inhibitory effect on the growth of H. pylori. CAPE, one
of the main medicinal components of propolis, is a competi-
O
N
OH
N
H
H
N
O
(46)
Amina et al. [100] have analyzed the interactions between PfPDF and actinonin (5) to explore their binding
modes with view to identify novel and more efficient antimalarial drugs. Replacement of the hydroxymethyl and n-pentyl
groups of the actinonin with hydroxyl and cyclopentyl-ethyl,
respectively, has resulted in most active compound (47) with
enhancement of binding energy from -24.73 to -35.11
kJ/mol.
O
HO
H
N
N
H
OH
N
O
(47)
6.3. PDF Inhibitor as Anticancer Agents

HsPDF has been proposed as a novel cancer therapeutic target [101]. Despite the slow kinetic properties of
HsPDF in an in vitro deformylation assay, it has been reported that small interfering RNA (siRNA) interference of
HsPDF decreases human cancer cell proliferation. Similarly, pharmacological inhibition with the PDF antibiotic
inhibitor actinonin (5) and its analogues results in mitochondrial membrane depolarization and promotes cell death
or proliferation arrest in a wide variety of cancer cells
[102]. Actinonin (5) has been reported to inhibit the growth
of HL60 and other human cell lines in vitro with IC50 values ranging from 5.4 to 13.5 M. In a leukemia cellinduced mouse tumor model (in vivo), mice were treated
with actinonin 100 g/mL/mice/day for first 3 days after
transplantation followed by three additional injections (injected every other day) at the same dose. On day 17, no
tumor growth was found in the actinonin-treated mice
[103]. Mona et al. [104] have investigated the anticancer
activity of actinonin (5) against Daudi and HL60 human
cancer cell lines and found the activity with an LC50 of 5.3
and 8.8 M, respectively.
6.3.1. Peptidic Inhibitor as Anticancer Agents
Mona et al. [105] has explored the potential of some
actinonin-based compounds as anticancer agents through the
inhibition of HsPDF activity. The compounds selectively
inhibited the 16 tumor cell lines (prostate cancer and lung
cancer) but not normal cells. The most potent compounds of
the series (48) and (49) have IC50 values ranging from 1 to
11 M against cell lines. The IC50 value for the same compounds against HsPDF assay was 0.069 M and 0.115 M,
respectively. Thus, suggesting that HsPDF enzyme may provide a novel selective target for anticancer therapy.
Sangshetti et al.
on breast cancer [106]. These inhibitors were previously

reported to show strong inhibitory activities against pathogenic bacteria. The KI values for the most potent compound
PMT497 (50) inhibiting the HsPDF was measured as 0.0295
0.0913 M. They also performed a cytotoxicity test for the
chemicals using two kinds of breast cancer cell lines (MDAMB231 and MDA-MB468). The cytotoxic IC50 values for
compound PMT497 (50) was 20.9 5.3 M against
MDAMB231 and 21.2 6.4 M against MDA-MB468 cell
lines.
H
N
N
H
HO
OH
HO
OH
HO
Hematoxylin
(51)
HO
O
HO
H
N
HO
O
(49)
Sang et al. have identified the four new potent HsPDF

inhibitors for the development of anticancer agents focused
OCH3
OCH3
OH
HO
Theaflavin OH
(52)
O
OH O
Puppurogallin
(53)
OCH3
OH
HO
N
H
PMT497
(50)
The same research group [108] has also synthesized

benzofuran-4,5-diones as novel and selective nonpeptidomimetic based inhibitor of HsPDF a new class of
antitumor agents. They investigated the cytotoxicity study
in a panel of 9 cancer cell lines, and assessed in vivo efficacy in a mouse xenograft model. The most active compounds (54) and (55) of the series were reported to have
IC50 value 6.1 M and 5.2 M, respectively, for HsPDF
enzyme. Thus, the derivatives of benzofuran-4,5-dione
scaffold may constitute a new class of potent antitumor
agents selective for HsPDF.
(48)
HO
OH
In an effort to develop novel non-peptidomimetic and

non-hydroxamic acid-based inhibitors of HsPDF, Christophe
et al. [107] have developed a high-throughput screening
(HTS) strategy using a fluorescence polarization (FP)-based
binding assay as the primary assay for screening chemical
libraries, followed by an enzymatic-based assay to confirm
hits. The cytotoxicity studies revealed that most of the confirmed hits have antiproliferative activity. The IC50 value in
the FP binding assay for most active hits hematoxylin (51),
theaflavin (52) and puppurogallin (53) have been found to be
2.7 M, 6.1 M, and 8.8 M, respectively.
O
N
H
N
6.3.2. Non-Peptidic Inhibitor as Anticancer Agents
HO
O
H
N
O
HO
HO
H
N
OCH3
CH3
O
Cl
Cl
Br
(54)
Br
(55)
7. IN-SILICO STUDIES OF PDF INHIBITORS

In-silico drug design is a rapidly growing tool in the area
of medicinal chemistry and proved its utility in recent years.
Crystal structures of proteins are the most common source of
structural information for drug design since high resolution
protein structures are available. The several crystal structures
for PDFs, co-crystallized with different inhibitors have been
reported. The various recent crystal structures of PDFs available in PDB databank are summarized in Table 1.
Drug-receptor studies have depicted that actinonin (5)
can bind into the active site of various PDFs, such as E. coli,
S. aureus, and P. aeruginosa. Despite minor differences in
the active site of PDFs and secondary structures, actinonin
(5) adopts the similar binding conformation in all of the PDF
enzymes for which co-crystallization data are available. The
interactions of actinonin (5) with E. coli Ni-PDF is shown in
(Fig. 9a). The metal-binding ion (Ni2+) is pentacoordinated
as two O atoms of the hydroxamate moiety form two bonds
with metal ion. The oxygen-nickel binding distances are 2.1
(the nitrogen-bound oxygen atom of the hydroxamate) and
2.3 (the carbonyl oxygen atom of the hydroxamate). Hydrogen bonds are made to the hydroxamate by the side
chains of His-132 and Glu-133. The hydrogen bonds are also
made between the main-chain NH of Ile-44 and the P1 carbonyl and also between the main-chain carbonyl oxygen and
NH group of Gly-89. The NH group of Gln-50 and Leu-91
form hydrogen bonds with P2 carbonyl group. The hydrophobic S1 pocket is delineated by the residues Ile-44 and
Table 1.
229
His-132 and is occupied by the n-pentyl side chain of actinonin (5). Similarly, inhibitor atoms at the P3 position are
solvent accessible, with one face of the pyrrolidine ring in
actinonin (5) packing against the side chain of Ile-44. In the
PDF-actinonin complex, a final hydrogen bond is made between the terminal alcohol group and the main chain carbonyl oxygen of Glu-87 [58].
7.1. Drug-Receptor Interactions for Antibacterial Agents
There are number of reports published on drug-receptor
interactions for PDF inhibitors as antibacterial agents. Here,
we have discussed the binding interaction of BB-3497 (6)
with E. coli Ni-PDF as a representative example. Researchers at British Biotech have elucidated the binding interactions of BB-3497 (6) to E. coli Ni-PDF (Fig. 9b). The metalbinding ion (Ni2+) is pentacoordinated as two O atoms of the
N-formyl-hydroxylamine form two bonds with metal ion.
The bond lengths between oxygen-nickel are 2.1 (the carbonyl oxygen atom of the N-formyl-hydroxylamine) and 2.3
(the nitrogen-bound oxygen atom of the N-formylhydroxylamine). The side chains of Glu-133 and Gln-50 and
the main-chain NH of Leu-91 have formed the hydrogen
bonding with N-formyl-hydroxylamine. The hydrogen bonds
are also made between the main-chain NH of Ile-44 and the
P1 carbonyl and also between the main-chain carbonyl oxygen and NH groups of Gly-89 and the P2 NH and carbonyl
groups. The hydrophobic S1 pocket is delineated by the
residues Ile-44 and His-132 and is occupied by the n-butyl
List of some crystal structures available in PDB for PDF, co-crystallized with various ligands.
Sr.
No.
PDB
Code
Organism
Metal Ion
Co-crystallized ligand
Release date
Ref.
1BSJ
E. coli
Co2+
(S)-2-(Phosphonoxy)caproyl-l-leucyl-p-nitro anilide
2000-04-15
[109]
2+
(S)-2-(Phosphonoxy)caproyl-l-leucyl-p-nitro anilide
2000-04-15
[109]
1BSK
E. coli
Zn
1G27
E. coli
Ni2+
2-[(Formyl-hydroxy-amino)-methyl]-hexanoicacid(1dimethylcarbamoyl-2,2-dimethyl-propyl)-amide
2001-10-17
[58]
1G2A
E. coli
Ni2+
Actinonin
2001-10-17
[58]
2+
Actinonin
2002-07-24
[39]
1LRY
P. aerogenosa
Zn
1S17
P. aerogenosa
Ni2+
2-(3,4-Dihydro-3-oxo-2H-benzo[b][1,4] thiazin-2-yl)-nhydroxyacetamide
2004-03-30
[110]
1Q1Y
S. aureus
Zn2+
Actinonin
2004-07-23
[111]
2+
Actinonin
2005-08-16
[112]
1SZZ
L. interrogans
Zn
2AI7
S. pneumoniae
Ni2+
Hydroxy-(3-phenylpropyl)amino methanol
2005-09-06
[46]
10
2EW5
H. pyroli
Co2+
4-{(1E)-3-Oxo-3-[(2-phenylethyl) amino]prop-1-en-1-yl}-1,2-phenylene
diacetate
2006-10-24
[113]
11
3E3U
M. tuberculosis
Ni2+
N-[(2R)-2-{[(2S)-2-(1,3-benzoxazol-2-yl) pyrrolidin-1yl]carbonyl}hexyl]-N-hydroxy formamide
2009-01-20
[61]
12
3U7N
S. aureus
Zn2+
N-((2R,4S)-2-butyl-5-methyl-4-(3-(5-methyl pyridin-2-yl)ureido)-3oxohexyl)-N-hydroxy formamide
2012-06-27
[114]
13
4E9A
H. pyroli
Co2+
2-Phenylethyl-(2E)-3-(3,4-dihydroxyphenyl) prop- 2-enoate
2013-04-24
[96]
14
15
1RL4
3G5K
P. falciparum
H. sapiens
Co
2+
(2R)-2-{[Formyl(hydroxy)amino]methyl} hexanoic acid
Co
2+
Actinonin
[99]
2009-04-07
[101]
side chain of BB-3497. These findings suggest that binding

interaction E. coli Ni-PDF-BB-3497 complex is very similar
to that of E. coli Ni-PDF-actinonin complex [58].
Sangshetti et al.
like Gly-52, Gln-57, His-156, and Glu-157. Actinonin (5)

fits on the HsPDF active site in a linear conformation, with
its backbone kept in place through hydrogen bonds with four
hydrogen donors/ acceptors in the main chain of HsPDF
(Val-51, Pro-111, Gly-113, and Glu-115) and hydrophobic
interactions (Glu-112, Ile-153, and His-156 amino acid residues). Comparison of actinonin-bound HsPDF to number of
PDFs has been elucidated and showed a similar conformation for actinonin (5), except for that in S. aureus [101].
7.4. QSAR Studies of PDF Inhibitors
Fig. (9). (a) Actinonin bound to the active site of E. coli Ni-PDF
(PDB ID: 1G2A); (b) BB-3497 bound to the active site of E. coli
Ni-PDF (PDB ID: 1G27); (c) Actinonin bound to the active site of
P. falciparum Co-PDF (PDB ID: 1RQC); (d) Actinonin bound to
the active site of H. sapiens Co-PDF (PDB ID: 3G5K).
The literature reveals that efforts are also made for designing of potent PDFs inhibitors using ligand based approaches. Jian et al. have reported the 3D-QSAR study of
pseudopeptidic hydroxamic acid PDF inhibitors (Fig. 10)
[115]. The study revealed that electrostatic and bulky group
substituent at R1 position and electropositive and small substituent at R2 position were favorable for the inhibitory activity. FlexX docking was also employed to investigate the
binding mode between PDF and its inhibitors and found that
hydrogen bond interactions might be an important factor for
the binding affinity of inhibitors in the hydrophobic cavity.
Based on 3D-QSAR model and FlexX docking, a series of
PDF inhibitors with high predictive activities have been designed and structure of most active inhibitor (56) has pIC50
value 9.73 and FlexX score-33.19 kJ/mol.
7.2. Drug-Receptor Interaction for Antimalarial Agents

O
The identification of P. falciparum PDF has suggested

the new target for antimalarial therapy. Amina et al. have
analyzed the interactions between the P. falciparum Co-PDF
and actinonin (5) to explore the binding modes with a view
to identify more efficient antimalarial drugs using molecular
docking software FlexX. The actinonin (5) forms several
hydrogen bonds with amino acid residues of the binding
pockets. The metal-ion of P. falciparum PDF (Co2+) is pentacoordinated as two O atoms of the hydroxamate moiety
form two bonds with metal ion. The hydroxamate moiety
also forms three hydrogen bonds with amino acid residues
like Gln-112, His-198, and Glu-199. The actinonin (5) backbone is kept in place by forming five hydrogen bonds with
amino acid residues like Ile-106, Ile-153, Gly-155, and Leu157 (Fig. 9c). The actinonin (5) is also stabilized by hydrophobic interactions with S1 residues which are the binding
site for the methionine side chain of the substrate Gly-155,
Leu-157, Ile-195, and His-198 [100]. The result confirms the
previous reports by Guilloteau et al. [35] where the interactions between the actinonin and four PDFs were studied to
determine their binding mode.
7.3. Drug-Receptor Interaction for Anticancer Agents
HsPDF is capable of removing formyl groups from Nterminal methionine of newly synthesized mitochondrial
proteins. Sindy et al. have reported the binding interactions
of HsPDF with actinonin (5) in order to explore potential of
HsPDF as a novel target for cancer (Fig. 9d). In the presence
of actinonin (5), Co2+ metal ion of HsPDF is pentacoordinated as it has formed two bonds with two O atoms of the
hydroxamate group. The hydroxamate moiety of actinonin
(5) also forms four hydrogen bonds with amino acid residues
HO
N
H
R2
R1
N
H
Fig. (10). General template structure of pseudopeptidic hydroxamic

acid PDF inhibitors.
Where R1=
N
H
N
H
N
H
N
H
N
HN
N
N
S
N
HN
H
N
S
HN
N
H
OH
Cl
N
S
HN
N
H
N
HN
N
H
N
N
H
Cl
N
S
F
H
N
N
N
H
N
N
N
HOH
N
H
N
N
NH
N
NH N
N
HN
NH
R2= H, R-OH, S-OH, R-OMe, S-OMe, S-OSO3H, S-F, R-F
O
HO
CH3
N
N
H
O
OH
Cl
N
H
O
(56)
OH
N
O
H
R1
H
N
O
R3
R2
Fig. (11). General template structure of reverse hydroxamate derivatives PDF inhibitors.
R2=
R3=
When
R1=
R3=
When
R 1=
R 2=
O
(57)
CH3
Ji et al. have performed the 2D and 3D-QSAR studies of

a series of published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives (Fig. 11) having
antibacterial activity against E. coli PDF [116]. This study
yielded some important structural information that can be
used for the design of novel PDF inhibitors. The study revealed that sterically bulky substituents like n-butyl or cyclopentyl-methyl group at R1 position, sterically moderately
bulky groups at R2 position and para-substituted phenyl
group at R3 position were beneficial for activity.
When
OHH
N
R1= n-Bu, Me, Et, n-Pr, (S) n-Bu, nPentyl, n-Hexyl, n-Heptyl, n-Octyl, i-Pr,
i-Bu, i-Pentyl, c-Pentylmethyl, c-Pentyl,
c-Hexylmethyl, Allyl, But-3-enyl, But-2ynyl, EtSCH2, Bn, Ph(4-Cl), (4MeO)PhCH2, 1-Piperidylmethyl
R2= Gly, Ala, Val, Leu, Cha, Ile, (R)tLeu, Pen(SMe), Cys(Bn), Ser, Val(OH), Val(-OMe), Asp(-Bn), Glu(Bn), Lys, Lys ( -NMe2), Arg, Phe, Phe
(4-Cl), Tyr, L-Tic, Pro
R3= OMe, OH, Me, Pyrrolidin-1-yl, Morpholin-4-yl, 4-Me-piperazin-1-yl, 4-Mepiperidin-1-yl, 4-Ac-piperidin-1-yl, 4EtO2C-piperidin-1-yl, 4-Bn-piperidin-1yl, N(Me)c-Hexyl, Decahydroquinolin-1yl, N(Bn)CH2CH2Ph, Ph, 2-Pyridyl, 2Furyl
Manish et al. have reported the 2D-QSAR study of sulfonyl and -sulfinyl hydroxamic acid derivatives and
demonstrated that the PDF inhibitory activity in cell free and
the whole cell system was increased with increase in molar
refractivity and hydrophobicity [117]. Itishree et al. have
performed comparative molecular field analysis (CoMFA)
analysis of -sulfonyl and -sulfinyl hydroxamic acid derivatives to figure out the structural requirements of PDF inhibitors belonging to non-peptidic class and to optimize their E.
coli peptide deformylase inhibitory activity [118]. On the
basis of spatial arrangement of field contribution, three novel
molecules were designed and predicted for PDF inhibitory
activity. The most active designed compound (57) has pIC50
value 1.3061 and predicted IC50 value 0.0494 M for E. coli
PDF.
231
O
N
H
OH
Very few reports are available on the pharmacophore development of PDF inhibitors. There is an urgent need for
developing common pharmacophore so that the designing of
various chemical classes of PDF inhibitors could be rationalized. Molecular docking and QSAR studies of existing PDF
inhibitors could help in developing a more potent and selective PDF inhibitor with lesser side effects and better pharmacokinetic properties.
8. CURRENT CLINICAL CANDIDATES
After initial validation of PDF enzyme as an antibacterial
drug target, tremendous progress has been made in the development of PDF inhibitors. Extensive preclinical studies
have been carried out for theses classes of compounds. Three
compounds, GSK-1322322, BB-83698, and LBM-415 have
been entered into clinical trials.
8.1. GSK-1322322
GSK-1322322 (58) (discovered by GlaxoSmithKline) is
novel PDF inhibitors of the pseudopeptidic class, which has
shown good safety and pharmacokinetic properties in a
Phase I clinical trial and promising proof of-concept results
in a Phase IIa study [119]. GSK-1322322 (58) is currently
being developed for the oral and intravenous treatment of
acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The
activity of GSK-1322322 (58) was tested against a global
collection of clinical isolates of H. influenzae (n= 2,370), M.
catarrhalis (n= 115), S. pneumoniae (n= 947), S. pyogenes
(n= 617), and S. aureus (n= 940), including strains resistant
to one or more marketed antibiotics. GSK-1322322 (58) had
an MIC90 of 1 g/mL against M. catarrhalis and 4 g/mL
against H. influenzae, with 88.8% of -lactamase-positive
strains showing growth inhibition at that concentration. All
S. pneumoniae strains were inhibited by <4 g/mL of GSK1322322 (58), with an MIC90 of 2 g/mL. Pre-existing resistance mechanisms did not affect its potency, as evidenced by
the MIC90 of 1 g/mL for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK-1322322 (58) was very
potent against S. pyogenes strains, with an MIC90 of 0.5
g/mL, irrespective of their macrolide resistance phenotype.
This PDF inhibitor was also active against S. aureus strains
regardless of their susceptibility to methicillin, macrolides,
or levofloxacin, with an MIC90 of 4 g/mL in all cases.
Time-kill studies showed that GSK-1322322 (58) had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a >3-log10 decrease in
the number of CFU/mL at 4 MIC within 24 h in 29 of the
33 strains tested.
In summary, GSK-1322322 (58) has the spectrum of activity and in vitro potency necessary for therapeutic use
against respiratory tract and skin and soft tissue infections.
Furthermore, its unique mode of action provides a clear ad-
Sangshetti et al.
vantage in the treatment of multidrug-resistant pathogens and

ensures lack of cross-resistance with any other marketed
antibiotics. This PDF inhibitor has completed early clinical
trials and has shown pharmacokinetic and safety parameters
warranting progression to Phase IIb studies. The antibacterial
potency of GSK-1322322 (58) suggests a valuable alternative therapy for the treatment of infectious diseases caused
by drug-resistant pathogens [120].
O
H
N
H
N
N
N
N
H
N
OH
GSK-1322322
(58)
8.2. BB-83698
BB-83698 (59) (discovered by British Biotech, in collaboration with Genesoft) has been investigated in Phase I
clinical trial for intravenous treatment of various bacterial
infections. This pseudopeptidic inhibitor showed potent in
vitro activity against S. pneumoniae with an MIC90= 0.5
g/mL, but less potent activity against S. aureus (MIC90= 8
g/mL) and H. influenza (MIC90= 16 g/mL). The subcutaneous administration to mice, the compound showed rapid
distribution to the lung, with 4-fold higher concentrations
than that in plasma [121]. The pharmacokinetic studies with
dose ranging from 10 to 50 mg/kg in mice, rats and dogs
exhibited biphasic pattern with moderate volumes of distribution in all species. The pharmacokinetic parameters were
consistent, predictable, and exhibited good allometric scaling
among all species (R2 > 0.98).
The Phase I study of BB-83698 (59) was explored at
eight dose levels ranging from 10 to 475 mg and was administered via 15 min intravenous infusion. The overall mean
clearance rate (CL) was approximately 238 130 mL/min,
with CL values ranging from 189 mL /min at a dose of 475
mg to 521 mL/min at the lowest dose. At the highest dose of
475 mg, an AUC/MIC ratio of 184 was achieved, based on S.
pneumoniae MIC of 0.25 g/mL, which is predicted to be
within the efficacious range (AUC/MIC 133) for once-daily
dosing derived from PK/PD studies [122]. The compound
was terminated from the study when British Biotech overtook by Vernalis (Financial Times, September 30, 2003).
Oscient has now purchased this compound but further clinical study is still considered to be discontinued [18].
O
O
O
N
O
N
H
O
N
OH
BB-83698
(59)
8.3. LBM-415
LBM-415 (60) (discovered Vicuron Pharmaceuticals, in
collaboration with Novartis, also called VIC-104959 or
NVP-PDF-713) is also a pseudopeptidic class of novel PDF

inhibitor targeting a large number of bacterial species. This
compound has been investigated in Phase I clinical trial as
oral administration. LBM-415 (60) has excellent in vitro
antibacterial activity against S. aureus (MIC90 = 2 g/mL), S.
pneumoniae (MIC90 = 1 g/mL), and E. faecalis (MIC90 = 4
g/mL). In pharmacokinetic studies, LBM-415 (60) showed
62% and 22-101% absolute oral bioavailability in mice and
rats, respectively, with no indication of absorption saturation
at higher doses. Oral administration of LBM-415 (60) exhibited similar efficacy in comparison to linezolid and
clarithromycin in S. aureus and S. pneumoniae systemic infection model. The pharmacodynamic study of LBM-415
(60) using a neutropenic mouse thigh model of S. pneumoniae showed a prolonged post-antibiotic effect (4.1-11.6 h).
The Phase I clinical study was performed to explore
LBM-415 (60) as a potential oral agent for community respiratory tract infections. Single oral doses ranging from 100
mg to 3000 mg were given in an ascending order, and the
compound was rapidly absorbed with Tmax (time of maximum
observed concentration) 1 h across all dose groups. Linear
pharmacokinetics were observed with dose -proportional
increase of maximum observed concentration (Cmax) and
mean terminal half life (T1/2) was ranged from 2 to 4.2 h. The
pharmacokinetic studies of LBM-415 (60) after food intake
revealed that while the Tmax was delayed (from 0.5 to 2 h)
and lower (from 15.5 to 6.7 g/mL), with no change in overall systemic exposure. A multiple dose study (250, 500, and
100 mg twice daily for 11 days) showed no accumulation
after 11 days with no significant differences in pharmacokinetic parameters. From the Phase I clinical trial study, the
overall profile of LBM-415 (60) supported a twice-daily
dosing regimen [11]. Recently, pharmacokinetics and unexpected safety issues of LBM-415 study have been reported
and revealed that the compound was well tolerated at low
doses, but at the highest dose, 1000 mg t.i.d. (target therapeutic dose), reversible cyanosis and low oxygen saturation,
attributable to methemoglobinemia, were detected on day 11.
Oxygen saturation was as low as 88% in one subject on day
11 [123].
O
N
F
H
N
O
N
O
N
OH
LBM-415
(60)
9. RESISTANCE ISSUE TO PDF INHIBITORS

PDF is now recognized as novel antibacterial target for
new generation, broad spectrum antibiotics. However, some
issues, including possible resistance mechanisms and anticipation of toxicity to human have to be addressed. PDF inhibitors have exerted bacteriostatic, not bacteriocidal activity, thus reducing their potential usefulness in the management of serious infections. The relative ease with which microorganisms have been able to develop resistance and the
multiple available mechanisms of resistance (mutations in
formyl transferase (fmt), tetrahydrofolate dehydrogenase
(folD) genes; and AcrAB/ToIC efflux pump) are worrisome
[124-127]. Despite these current liabilities, PDF is still considered as an extremely attractive target for antibacterial
agents as the resistance mechanisms are newer one. For example, fmt mutants have shown systematically reduced
growth rate compared to the wild type.
The most serious reservation for the use of PDF inhibitors as antibacterial could come from the recent identification of an HsPDF. The existence of this enzyme undoubtedly
raises the issue that treatment with such compounds could
result in toxicity. However, the PDF inhibitors inhibit the
growth of human cell lines at high concentrations and have
excellent safety profiles in the preclinical development. The
clinical candidates GSK-1322322 (58), BB-83698 (59), and
LBM-415 (60), appear well tolerated in a Phase I study. This
selectivity suggests strongly that PDF inhibitors will not be
toxic to humans at its clinical dose [128].
REFERENCES
[1]
[2]
[3]
[4]
[5]
[6]
[7]
CONCLUSION
In last few years, PDF enzyme has been emerged as an
important target in antibacterial drug discovery. Different
types of PDF have also been identified. The threedimensional structures and co-crystal structures of PDF enzyme have been well characterized and established. The active binding sites in the PDF enzyme for inhibitors have also
been well identified. These results led to the development of
PDF inhibitors as a new class of antibacterial agents. Three
PDF inhibitors as antibacterial agents, GSK-1322322 (Phase
II), BB-83698 (Phase I), and LBM-415 (Phase I) have entered into clinical developments. The further clinical studies
of BB-83698 and LBM-415 have been stopped due to unknown reasons. Thus, only in case of positive results of
Phase II clinical study of GSK-1322322 will validate the
PDF as a target for antibacterial drug discovery.
Some recent reports about the involvement of PDF in
human cancer and malaria parasites have gained a great deal
of attention from scientific community. The active binding
sites of human PDF and plasmodium PDF have also been
well identified and established. Some chemical classes of
PDF inhibitors as antimalarial and anticancer are developed
based on drug-receptor interactions. However, the clinical
utility of these PDF inhibitors need to be established in the
future. In short, PDF has been extensively explored as an
attractive target for antibacterial, antimalarial and anticancer
drug discovery. Further results from clinical trials will ultimately decide the fate of PDF as a versatile drug target in
drug discovery.
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CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of interest.
ACKNOWLEDGEMENTS
The author JNS is grateful to Department of Science and
Technology (DST), New Delhi, India for Fast Track Project
(SR/FT/LS119/2012). The authors are also thankful to the
Mrs. Fatma Rafiq Zakaria, Chairman, Maulana Azad Educational Trust and Dr. Zahid Zaheer, Principal, Y.B. Chavan
College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431 001 (M.S.), India for constant support and providing necessary facilities.
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Peptide Deformylase: A New Target in Antibacterial, Antimalarial and

Keywords: Antibacterial, anticancer, antimalarial, clinical developments, peptide deformylase.

promising molecules. Alternative strategies must therefore

Peptide Deformylase: A New Target

deformylase (PfPDF) as a drug target, new antimalarial

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

the carbonyl oxygen of the formyl group. The carbonyl

216 Current Medicinal Chemistry, 2015, Vol. 22, No. 2

and among other eukaryotes [28, 29]. PfPDF is found in the

PDFs, have been cloned and over expressed. PDFs of all

Peptide Deformylase: A New Target

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

Escherichia coli, Haemophilus influenza,

Bacillus subtilis, Mycoplasma pneunomiae,

Fig. (3). A phylogenetic tree for three distinct classes of PDFs.

4.1. Three-Dimensional Structure of Bacterial PDFs

coli and S. aureus proteins is only 23% [35]. Generally,

218 Current Medicinal Chemistry, 2015, Vol. 22, No. 2

its enzymatic activity [16]. The approximately 30% sequence

Peptide Deformylase: A New Target

other PDFs. Despite HsPDF lacking true S2and S3 substrate

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

in size and shape among PDFs from various Gram-positive

The S2 pocket is an open tunnel-like space pointing out

The S1 pocket of PDF is mostly hydrophobic pocket and

In contrast, the S3 pocket of PDFs is the least conserved

4.4. Substrate-Binding Pockets

220 Current Medicinal Chemistry, 2015, Vol. 22, No. 2

preferably deformylated by E. coli PDF. The study revealed

4.5. Metal-Binding Site

Actinonin is the first reported naturally occurring PDF

Fig. (7). Proposed general structure for PDF inhibitors.

Peptide Deformylase: A New Target

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

Fig. (8). Classification of PDF inhibitors.

In this system, activation of formyl peptide receptors (FPR)

6.1.1.2. H-Phosphonate Derivatives

222 Current Medicinal Chemistry, 2015, Vol. 22, No. 2

N-formyl-N-hydroxylamine exhibit appreciable antibacterial

6.1.1.3. Aldehyde Derivatives

6.1.2.2. P2-Pyrrolidine Containing Inhibitors

6.1.2. Pseudopeptidic Inhibitors as Antibacterial Agents

Researchers at Vicuron (formerly Versicor) and Novartis

Peptide Deformylase: A New Target

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

Scientists at Novartis also designed and synthesized the

6.1.2.3. P2-Dihropyrrole Containing Inhibitors

6.1.2.4. P2-Methylenepyrrolidine Containing Inhibitors

Oxazolidine moiety is an important building block for

224 Current Medicinal Chemistry, 2015, Vol. 22, No. 2

6.1.2.6. P2-Azaamino Containing Inhibitors

6.1.3.2. Bicyclic Hydroxamic Acid Derivatives

The group at Novartis has identified and synthesized new

6.1.3. Non-Peptidic Inhibitors as Antibacterial Agents

6.1.3.3. -Sulfonyl- and -sulfinylhyrdoxamic Acid Derivatives

Peptide Deformylase: A New Target

Current Medicinal Chemistry, 2015, Vol. 22, No. 2

6.1.3.7. Isoxazole Derivatives

oxidation of sulfur of benzthiazole ring to sulfone resulted in

Fieulaine et al. have designed and developed a series of

6.1.3.5. Benzamide and Aryl Ether Derivatives

The group at GlaxoSmithKline has published a patent

6.1.3.6. Benzothiazole Derivatives