International Journal of Peptide Research and Therapeutics

https://doi.org/10.1007/s10989-017-9650-0

Peptide Therapeutics Versus Superbugs: Highlight onCurrent

Research andAdvancements
KrishnanandNagarajan1 SathishKumarMarimuthu1 SelvamaniPalanisamy1 LathaSubbiah1

Accepted: 13 November 2017

Springer Science+Business Media, LLC, part of Springer Nature 2017

Abstract
Antibiotics have saved several millions of lives, but its persistent use of antibiotics in the treatment of various infections,
whether bacterial, fungal, viral or parasitic has lead to the development of antibiotic resistance. The rapid emergence of
antibiotic resistant strains poses a serious challenge to existing antimicrobial therapies. Due to the increase in drug-resistant
pathogens and failure of antibiotics the urgent need for the discovery of novel antimicrobials has been continuously empha-
sized in the global forum. Here we review about antimicrobial peptides (AMPs), their structural insights and recent develop-
ments. We had summarized the major classes, mechanism of action and biophysical parameters that modulate therapeutic
potency of AMPs. Also, we had briefed the challenges involved in developing therapeutic peptides and the global market
potential for peptide therapeutics.

Keywords Antimicrobial peptide Therapeutic Resistance Mechanism Biophysical parameters Global market

Introduction bacteria. The threat levels were categorized based on spe-

Antimicrobial resistance (AMR) is one of the most serious
health threats emerging globally. This poses the greatest
challenge in treating common infectious diseases; endanger
public health and efficacy of antibiotics, which results in
patient morbidity, mortality and increased health care costs
(Izadpanah and Khalili 2015; Long etal. 2017; Elliott etal.
2017). This escalating threat to global public health requires
immediate attention and action across all parts of the world.
An ever-increasing rate in the degree of resistance and com-
plexity of infections today has questioned the credibility and
effectiveness of current antibiotics in treating severe infec-
tions (Ventola 2015; Harten etal. 2017).
In the early of 2017, WHO has published a global prior-
ity pathogen list containing 12 drug-resistant bacteria, for
which new antibiotics are urgently required. This report has
insisted the importance and pressing need for developing
new antibiotics against multi-drug resistant gram-negative
* Krishnanand Nagarajan
krishwrites@gmail.com
1
Department ofPharmaceutical Technology, University
College ofEngineering, Anna University, Bharathidasan
Institute of Technology Campus, Tiruchirappalli,
TamilNadu620024, India
cies and the type of resistance: critical, high and medium.
Carbapenem-resistant Acinetobacter baumannii, Pseu-
domonas aeruginosa and carbapenem cum 3rd generation
cephalosporin resistant Enterobacteriaceae (Klebsiella
pneumonia, Escherichia coli, Enterobacter sp., Serratia
sp., Proteus spp., and Providencia sp., Morganella sp.)
respectively were stacked in the critical tire. It should also
be noted that in a similar kind of report published by CDC,
USA in 2013, Clostridium difficile, Carbapenem-resistant
Enterobacteriaceae and Neisseria gonorrhoeae were listed
in the urgent category, requiring more attention, monitoring
and prevention activities (Antibiotic/Antimicrobial 2017). A
very recent research has discovered that Klebsiella species
is a major causative in most morbidity and mortality cases
in a global scale and is a potent threat to public health. It has
been noticed that many strains of this bacteria are increas-
ingly gaining resistance, thus making infections much harder
to treat (Antibiotic/Antimicrobial 2017; Long etal. 2017).
Randomized and improper administration of antibiotics
is the primary cause for the development of drug-resistance
pattern in bacteria. Overusing or misusing antimicrobial
drugs make resistance to develop at a faster pace. Patient
non-adherence to prescribed medications, non-therapeutic
use of antibiotics in livestock, poultry and agricultural
operations adds as an additional reason for the development

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of resistant to antibiotics (Elliott et al. 2017). Thus the
growing antibiotic resistance and the decline in the rates of
novel drug discovery, drive the researchers to investigate on
new non-chemical antibacterial drugs to combat infectious
diseases, especially those caused by multidrug-resistant
(MDR) bacterias (Hoagland etal. 2016). It is definite that
Antimicrobial peptides (AMPs) will emerge as promising
alternatives to conventional antibiotics, owing to their rela-
tively simple methods of synthesis and modification. Recent
advancements in biotechnology have enabled synthesis of
precise AMPs (Elliott etal. 2017; Hoagland etal. 2016).
Antimicrobial peptides (AMPs) play a vital role in the
defense mechanisms of most organisms. They were also
referred to as host defense peptides in higher eukary-
otes (vertebrates, invertebrates, and plants). Antimicrobial
peptides contribute to the innate immunity. These peptides
were usually constituted with 540 amino acids and have
molecular weight of less than 10kDa (Hoagland etal. 2016;
Patel and Akhtar 2017). They function as natural antibiotics
and evade the infectious pathogens. Currently, many stud-
ies have reported novel functions such as skin regeneration,
antineoplastic effects, anti-tumor, wound healing, and others.
This review will provide a brief overview on current updates
regarding AMPs as therapeutics (Figs.1, 2, 3 and 4).
Structural Insight andAMPs Classes
AMPs universally display similar fundamental properties
such as cationic nature, amphipathicity, and hydrophobicity;
thus its possible to classify them only based on their second-
ary structure. Based on the types of secondary structures and
Bomans classification AMPs are grouped into four families:
, , , and non- respectively. Further, the Eukaryotic
Fig.1Briefing, the timeline of antibiotic deployment and resistance,
observed. Source: Centers for Disease Control and Prevention, US
Department of Health and Human Services, Atlanta, GA, 2015
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International Journal of Peptide Research and Therapeutics
Fig.2Structural diversification of 2818 AMPs in the APD database,
Source: Antimicrobial Peptide DatabaseUNMC, (http://aps.unmc.
edu/AP/main.php)
antimicrobial peptides can be categorized into cationic (e.g.:
defensins, cathelicidins, cecropins, thionins) and anionic
(Maximin, dermcidin) peptides.
Type I (Helical Peptides)
Alpha-helical peptides are the abundant and widespread
class of cytolytic AMPs with amphipathic and alpha-helical
domains that enable efficient interactions with the biologi-
cal membrane. Cecropin B, Cap11, Melittin, Cecropin P1,
Cap18, and magainins are some of the well-known peptides
of this class (Ebbensgaard etal. 2015). The membrane-bind-
ing motif of an amphipathic helix is formed by a sequence
of linear amino acid chains with a recurrence of polar and
apolar residues for every three to four residues along the
structure. This structure, with the polar side chains aligned
along one side and the hydrophobic residues along the oppo-
site side of the helical coat, allows an optimal interaction of
these peptides with the amphiphilic structure of the biologi-
cal membrane. The majority of the AMPs characterized so
far belong to this group of -helical peptides. Hydrophobic-
ity and helicity are critical parameters that govern the bio-
logical activities of -helical peptides. The hydrophobicity
and helicity of a peptide can be modulated by d-amino acid
substitution approach to form d- and l-diastereomeric pep-
tides, which in turn exhibit an increased peptide specificity,
stability, stronger antimicrobial activity and lower cytotoxic-
ity against healthy cells (Huang etal. 2014).
Type II (Beta Sheet Containing Peptides)
The beta pleated peptide family usually contains small,
cysteine-rich -strands containing peptides and are widely
distributed in the animal kingdom. AMPs with beta-strands
are semi or cyclic molecules whose structures are stabilized
by one to three intramolecular cysteine disulfide bridges.
Molecules of the -sheet peptide families include defensins,
tachyplesins, protegrins, bactenecin, dodecapeptides and
International Journal of Peptide Research and Therapeutics
Fig.3Modes of action of antimicrobial peptides. AMPs exert direct
neutralizing effects on bacterial pathogens which result in membrane
disruption or act upon internal targets of bacterial cells. In addition
to the direct mode of action, AMPs also mediate cells for acquired
Fig.4Distribution of FDA approved therapeutic peptides and pro-
teins based on routes of administration. Source: THPdb database
(http://crdd.osdd.net/raghava/thpdb/roa.php)
others (Miyasaki and Lehrer 1998). These peptides range
between 16 and 18 residues in length and exhibit broad spec-
trum antimicrobial activity and appear to function by mem-
brane disruption. They were also found to possess antiviral
activity against HIV-1 (Sitaram and Nagaraj 1999). Mol-
luscan defensins have initially been characterized in mussel
species, and a variety of different defensins were also then
immunity (neutrophils, t-cells, macrophages) to regulate inflam-
mation and increase bacterial clearance. Adapted from Jirku et al.
(2015). Antimicrobial peptides in human sepsis
reported in oysters, this includes the Cysteine-stabilized
defensin and big defensin AMP families (Schmitt etal.
2016). Structurefunction relationship studies in defensins
have revealed that the number of disulfide bridges and the
cysteine spacing has a significant effect on the antimicrobial
efficacy (Sharma and Nagaraj 2015).
Type III (Peptides withOverrepresentation
ofCertain Amino Acids)
A limited number of AMPs fall under this class of peptides
and usually differ from other classes due to lack of classical
secondary structure. These peptides distinguish itself with
an unusually high content of a specific amino acid, often
proline, tryptophan, histidine, and arginine. The conforma-
tions of these peptides are characterized by having minimal
structural constraints and adapt more extended structures.
Penaeidins, crustacean antimicrobial peptide with molecular
masses ranging from 5.5 to 6.6kDa, is characterized by an
over-representation of proline residues in their NH2-terminal
domain and by six cysteine residues in their COOH-terminal
domain (Destoumieux etal. 1997). Mytimacin-AF is another
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such kind of peptide characterized from a land-living mol-
lusk A. fulica, a novel cysteine-rich, cationic peptide com-
posed of 80 amino acid residues which include ten cysteines
(Zhong etal. 2013). The unusual amino acid composition
of these AMPs has directed the researchers to set down the
role of multiple tryptophan residues in its biological activity
as well as its interactions with model biological membranes
(Pasupuleti 2009).
Type IV (Peptides withLooped Structure andSingle
Bond)
This class of peptides is characterized by their looped struc-
ture imparted by the presence of a single bond (disulfide
or amide or isopeptide bond). This class of peptides differs
from the Type II peptides in having only single disulfide
bond and antiparallel -sheet orientation. Lantibiotics
belonging to this class are extensively studied due to their
unique biochemistry, genetic regulation, and a variety of bio-
logical functions (Pasupuleti 2009). The loop AMPs (e.g.,
bactenecin), adopt a loop formation with one disulfide bridge
(Seo etal. 2012). Thanatin, a 21-residue antimicrobial pep-
tide, similar to brevinin family contain C-terminal disulfide
loop exhibit broad range of activity against bacteria. This
class of peptides holds considerable potential to combating
existing and emerging infectious diseases because they are
short in size, easy to synthesize and proteolytically stable
(Pasupuleti 2009; Seo etal. 2012).
Mechanisms ofAction: How Do They Do It?
At Present several models are accounting for the antimicro-
bial peptide-induced killing of microbial cells. The widely
proposed and well-established mechanism of action for the
destruction of microorganisms by antimicrobial peptides rely
on membrane destabilization and disruption. Till date, three
models of membrane permeabilization have been proposed
in favor of: the BarrelStave, Toroidal and Carpet mod-
els. Most of these are thought to exert bactericidal effects
by forming pores in bacterial membranes, but their exact
molecular mechanism of action remains unclear. Moreover,
non-membrane or non-lytic AMPs in support with experi-
mental evidence have also been described which operate
through interacting with specific molecular targets (Scocchi
etal. 2016).
Membrane Permeabilization Mechanism
The BarrelStave Model was the first proposed one, describ-
ing a device in which antimicrobial peptides form a barrel-
like pore in the cell membrane via inserting themselves into
membrane as an individual or their complexes being the
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International Journal of Peptide Research and Therapeutics
staves spanning the membrane. The hydrophobic surface of
AMPs binds with the membrane lipid core, pointing out-
wards towards the acyl chains of the membrane whereas
the hydrophilic surfaces pointing inward thus creating a
transmembrane pore. This model has been suggested e.g.
for dermcidin.
In the toroidal pore model, the AMP inserts maintain a
parallel orientation to the bilayer normal and interact with
the membrane lipids to form a toroidal pore or worm-hole
channels (Pushpanathan etal. 2013; Li etal. 2017). The
membrane-spanning pore was estimated to be in size range
of 23nm (20.5nm as internal diameter and 31nm at
the rim) (Leontiadou etal. 2006). The typical AMPs such as
magainins, melittin and protegrins identified from an Afri-
can clawed frog, bee venom and porcine leukocytes respec-
tively were found to adapt this mode of action (Rashid etal.
2016; Li etal. 2017).
Carpet model stands last in the transmembrane pore-
forming mechanisms of antimicrobial peptides. They act
by accumulating on the bilayer surface in a monomeric/oli-
gomeric forms and reorient themselves in a manner, their
hydrophobic surface of the peptides face toward the lipid
side and the hydrophilic surface toward the phospholipid
head groups. On attaining a threshold concentration, sur-
face-oriented peptides permeate/disintegrate the bilayer in
a detergent-like manner and disrupting the bilayer curvature.
This model explains the activity of antimicrobial peptides
such as dermaseptin, cecropin, ovispirin and aurein 1.2
(Wang etal. 2015; Shahmiri etal. 2015; Li etal. 2017).
Apart from these models, molecular electroporation, sink-
ing raft, interfacial activity and lipocentric pore formation
models do exist, providing insight about interaction of small,
unstructured and compact peptides with lipid bilayer, which
lack membrane spanning capacity to form a pore directly
(Hamoen and Wenzel 2017). Latest reports of hexapeptide
(RWRWRW-NH2) and lipopeptide antibiotic daptomycin
have strengthened the fact that many lytic AMPs are non
pore formers; rather induce bacterial lysis by inhibiting cell
wall synthesis and interacting with fluid membrane micro-
domains thus delocalizing phospholipid architecture (Hen-
derson etal. 2016; Schmitt etal. 2016a, b).
In order to thoroughly understand the mode of action
of AMPs and subsequent cellular events, characterization
of these molecular processes is very important (Lee etal.
2015). AMPs -membrane interaction, destabilization and
damage is the crucial play in the destruction of microbes.
Optical biosensor technology has enabled characterizing
membrane interactions by quantitation of binding events
(Hirst etal. 2016). Surface plasmon resonance (SPR) is
the most commonly used optical biosensor technology
employed vastly for investigating membrane-mediated
events. At present, a number of advanced and promising
biosensors such as dual polarisation interferometry (DPI),
International Journal of Peptide Research and Therapeutics
plasmon waveguide resonance spectroscopy (PWR) and
optical waveguide light mode spectroscopy (OWLS)have
been developed, which provides an advantage of simultane-
ous measurement of structural changes and mass binding
thus facilitating to observe membrane structure changes dur-
ing peptide and protein binding (Lee etal. 2015; Hirst etal.
2016; Jirku etal. 2015).
A recent study using DPI have provide a new insight into
the membrane-penetrating property of penetratin and R8K-
biotin on membrane bilayer structure during binding and
insertion. Three distinct states namely a labile surface-bound
state, securely bound intermediate and membrane disrup-
tion following translocation were observed and the kinetic
parameters were also investigated (Jirku etal. 2015). In a
similar study the correlation between structural domain/
motif and membrane-binding characteristics of maculatin-
related peptides was seen (Sani etal. 2015). Thus helping
to develop deeper understanding about mechanisms of anti-
microbial peptides (AMPs) and design of novel and highly
selective antibacterial drugs (Sani etal. 2015; Choi etal.
2016).
Nonmembrane Permeabilizing Modes ofAction
There are widespread shreds of evidence indicate that anti-
microbial peptides, apart from their membrane-permeabi-
lizing mode of action, also operate through interacting with
intracellular targets. Examples of the intracellular activity
include, inhibition of DNA and protein synthesis, interfer-
ing with protein folding and key metabolic enzymes, and
inhibition of cell wall synthesis and septum formation. The
non-lytic and non-membrane permeabilizing peptides with
specificity over molecular targets have attracted substantial
attention as promising antibiotics for therapeutic applica-
tions and disease control (Bechinger and Gorr 2016). Repre-
sentative examples include Polyphemusin (horseshoe crab),
Pleurocidin (winter flounder) and Tritrpticin (mammalian
bone marrow). The following will brief on less documented
internally acting AMPs (Tables1, 2, 3, 4 and 5).
In 2016, Mario etal. reported on the killing mechanism
of Bac7135, a novel proline-rich AMP of cathelicidin fam-
ily found to selectively and comprehensively inhibiting
protein synthesis by interacting with 70s ribosome and
chaperone proteins (Mardirossian etal. 2014). Further,
insect-derived Drosocin, Oncocin, Pyrrhocoricin, Apidae-
cin and the cathelicidin-like Bactenecin and PR-39 from
mammals follow the same mechanism to inhibit bacte-
rial protein synthesis (Mardirossian etal. 2014; Limoli
etal. 2014). Further, were A human cathelicidin LL-37
was found to interact with DNA and disrupts normal DNA
replication thereby inducing mucA mutations in P. aerugi-
nosa, which is a key for phenotypic change from a non-
mucoid to a mucoid appearance, which directly correlates
with worsening of clinical prognosis and cause of death in
CF patients (Limoli etal. 2014). Similarly, LBP6A dem-
onstrated interactions with DNA and DNA polymerase
invitro and was proven effective against many Gram-neg-
ative bacteria, Gram-positive bacteria, and the yeast Can-
dida albicans (Nam etal. 2014). Like defensins, fungal
plectasin, eurocin, and copsin inhibit cell wall synthesis
by binding to lipid II (Wang etal. 2015; Nam etal. 2014).
Biophysical Parameters Capable
ofModulating Therapeutic Potency ofAMPs
While thinking about therapeutic peptides, the fundamen-
tal issues that need to be addressed are peptide potency,
stability, selectivity, sustainability, and targetability (de
Oliveira Dias and Franco 2015; Lomakin etal. 2015). It
has now been recognized that biophysical properties such
as amino acid composition, amphipathicity, hydrophobic-
ity, charge, peptide sequence, pI, net charge at physiologi-
cal pH, polar angles and post-translational modifications
contribute significantly to the interaction and insertion of
AMPs with the target cells (Wang 2012).
Peptide Sequence andAmino Acid Composition
The sequence length and composition are most important
parameters determining the activity of an AMP because
a minimum of 78 amino acids are required to form an
amphipathic structure of a peptide molecule. The size of at
least 22 amino acids is necessary for an alpha-helical AMP
to adapt a BarrelStave model of bacterial membrane per-
meabilization, while it is eight amino acids for -sheet
AMPs (Deslouches etal. 2005; Bahar and Ren 2013a, b).
Berthony and his coworkers engineered LBU (12 residue
peptide) by increasing its peptide length beyond two LBUs
(WLBU2 peptide 24 residue peptide) and substituted Trp
residues in the hydrophobic domains displayed elevated
antibacterial selectivity and saline tolerance (Deslouches
etal. 2005; Bahar and Ren 2013a, b). 18-mer peptide RI18
which is an analogue of PMAP-36 exhibited excellent
activity against both bacteria and fungi, and a reduced
hemolytic activity was observed in comparison to parental
peptide PMAP-36 and melittin. The selectivity indexes of
RI18 peptide against fungi and bacteria were improved
108 and 19-fold, respectively, compared to PMAP-36 (Lyu
etal. 2016). The majority of the AMPs analyzed contain
the highest content of Lys, Gly, Arg and Leu, and least
of Met, Trp, His, Asp, Glu, and Tyr (Dziuba and Dziuba
2014).
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 International Journal of Peptide Research and Therapeutics

Table1A brief on structural and functional aspects of recently published peptides

Structural Class PDB/APD ID Name Peptide sequence Activity Reference

Alpha-helix 5MMK HYL-20 GILSSLWKKLKKIIAK Antibacterial and Neuta etal. (2017)

antibiofilm
5MML HYL-20k GIMSSLMKKLAAHIAK Antibacterial and Neuta etal. (2017)
antibiofilm
2N1C PvHCt FEDLPNFGHIQVKVFNHGEHIHH Antifungal Petit etal. (2016)
AP02895 Natto peptide SMATPHVAGAAALILSKHPTWTNAQVRDRLES- Anti-Gram positive Kitagawa etal. (2017)
TATYLGNSFYYGK
AP02891 Dendropsophin 1 NLLNDALGTVNGLLGS Anti-Gram positive Triana-Vidal etal.
and anti-Gram (2017)
negative
AP02883 Codesane GMASLLAKVLPHVVKLIK Anti-Gram positive, ujov (2014)
anti-Gram negative
and antifungal
Beta sheet containing AP02728 Sviceucin CVWGGDCTDFLGCGTAWICV Anti-Gram positive Li etal. (2015]
peptides AP02627 Ep-AMP1 CVLIGQRCDNDRGPRCCSGQGNCVPLPFLGGVCAV Anti-Gram positive, Aboye (2015)
anti-Gram negative
Peptides with over- AP02854 SpPR-AMP1 GYFPGRPPFPRPFPRPPSRPFPRPPFPGPFPRPYPWR Anti-Gram positive, Imjongjirak etal.
representation of anti-Gram negative (2017)
certain amino acids AP02742 ArmadillidinQ GHLGRPYIGGGGGFN- Anti-Gram positive, Verdon etal. (2016)
RGGGFHRGGGFHRGGGFQSGGGFHRGGGFHSGGS- anti-Gram negative
FGYR and antifungal
AP02626 C. livia Cathelici- LIQRGRFGRFLGRIRRFRPRINFDIRARGSIRLG Anti-Gram positive, Yu etal. (2015)
din 2 anti-Gram negative
and antifungal
AP02601 BnPRP1 Pro-rich PPIQNPSMAPPTQNPYGQPMTPPTQNPYGQPMAPP Anti-Gram+ and Cao etal. (2015)
Gram, antifungal
Peptides with looped AP02731 Panusin SYVGDCGSNGGSCVSSYCPYGNRLNYFCPLGRTC- Anti-Gram positive, Montero-Alejo etal.
structure and CRRSY anti-Gram negative (2017)
single bond and antifungal
AP02605 Defensin-TK SPAIWGCDSFLGYCRLACFAHEASVGQKECAEGMLC- Anti-Gram positive, Shen etal. (2014)
CIPNV anti-Gram negative
and antifungal
AP02852 OsDEF7 RHCLSQSHRFKGMCVSSNNCANVCRTESFPDGECK- Anti-Gram Positive, Tantong etal. (2016)
SHGLERKCFCKKVC anti-Gram negative
and antifungal
AP02853 OsDEF8 RTCESQSHRFKGPCARKANCASVCNTEGFPDGYCHG- Anti-Gram positive, Tantong etal. (2016)
VRRRCMCTKPCP anti-Gram negative
and antifungal

Hydrophobicity andAmphipathicity charged amino-acid on the hydrophobic surface, signifi-

Hydrophobicity and amphipathicity are the two inevita-
ble structural features that determine the overall activity
of an antimicrobial peptide and contribute for the degree
of peptide partitioning and self-promoting uptake across
the lipid bilayer membranes respectively. Hydrophobic
moment (MH) is a quantitative measure of amphipathic-
ity and usually calculated as the vector sum of individual
amino acid hydrophobicities, normalized to an ideal helix.
An increase in hydrophobic moment correlates to increased
permeabilization of the target cell membrane. The correla-
tion between antimicrobial activity and toxicity resides in
cell selectivity. The cationic property of most AMPs con-
tributes to cell selectivity because the bacterial membrane
is more negatively charged than that of a mammalian cell
membrane.(Edwards etal. 2016; Liu etal. 2016; Hollmann
etal. 2016) Trichogin, a short peptaibol on modifying its
hydrophobicity and amphipathicity by introducing positively
cantly improved binding capacity and selectively in killing
T67 cancer cells without affecting healthy normal cells.(Liu
etal. 2016; Dalzini etal. 2016)Many structurefunction
relationship studies have revealed that more the peptide
being amphipathic, more the hemolytic index. Hence, the
critical parameter for all therapeutic AMPs, to maintain the
hydrophobichydrophilic balance for an enhanced potency
and better selectivity (Liu etal. 2016; Hollmann etal. 2016;
Dalzini etal. 2016).
On the other hand, AMPs with extreme hydrophobicity
exhibit poorer antimicrobial activity and higher hemolytic
toxicity in mammals have also been reported. Basically a
lytic AMP must fulfill two major criterias in terms of hydro-
phobicity; (i) The peptide must remain soluble in water and
biological fluids to enable rapid transport and accessibility
to the target microbes (low hydrophobicity is required) and
(ii) Simultaneously the peptide should be able to interact
with the hydrophobic region of the lipid bilayer in order to

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International Journal of Peptide Research and Therapeutics

Table2Summary of cationic antimicrobial peptides and their mechanisms of action

Presumed activity Peptide Mechanism of action References

Membrane-disruptive Nisin, daptomycin Pore former Brogden (2005), Le etal. (2015)

Alamethicin BarrelStave (Helical-Bundle) AlKhatib etal. (2014)
Magainin, mellitin, MSI-78 model Brogden (2005), AlKhatib etal. (2014)
Cecropin, dermaseptin, Toroidal pore (Wormhole, disk) model Brogden (2005), AlKhatib etal. (2014)
caerin, ovispirin
Indolicidin Carpet model AlKhatib etal. (2014)
Human AMP LL-37 Aggregate model
carpet/toroidal pore
Membrane nondisruptive Buforin II DNA synthesis AlKhatib etal. (2014)
Indolicidin, PR39, HNP-1 DNA synthesis, cell division AlKhatib etal. (2014), Ingham and Moore
(2007)
Pleurocidin derivative RNA, Protein Synthesis AlKhatib etal. (2014)
PR39, dermaseptin Protein synthesis, cell septum AlKhatib etal. (2014)
CP10A formation Friedrich etal. (2001), Le etal. (2016]
Dermaseptin RNA, protein Synthesis Boman etal. (1993)
Pyrrhocoricin, drosocin Protein synthesis Brogden (2005), AlKhatib etal. (2014)
Apidaecin Disruption of DnaK (chaperone) AlKhatib etal. (2014)
Pep5, daptomycin activity Le etal. (2015)
Mutacin 1140 Cell wall lytic enzyme release Mller etal. (2016)
Microcin 25, PR-39, PR-26 Lipid II sequestion AlKhatib etal. (2014)
Histatins Cell septum formation AlKhatib etal. (2014)
Coprisin Inhibits enzymatic activity Mller etal. (2016)
Magainin 2 Apoptosis-induction Mller etal. (2016)
Papiliocin RecA activation in E. coli Mller etal. (2016)

Table3Antimicrobial peptides launched against infectious diseases. Source: THPdb database (http://crdd.osdd.net/raghava/thpdb/roa.php)
Name Peptide sequence Category Company

Aldesleukin MAPTSSSTKKTQLQLEHLLL Antineoplastic agents, Anti-HIV agents Chiron Corp

Drotrecogin alfa Heavy chain: LIDGKMT Antisepsis Eli Lilly and Company
Enfuvirtide YTSLIHSLIEESQNQQEKNE HIV fusion inhibitors Trimeris, Roche
Gramicidin D VGALAVVVWLWLWLWX Anti-bacterial agents, anti-infective, topical, Sanofi
antibiotic
Interferon alfa-n1 CDLPQTHSLGSRRTLMLLAQ Antiviral agents, immunologic factors, GlaxoSmithKline
immunosuppressive agents
OspA lipoprotein MKKYLLGIGLILALIACKQN Vaccine targeting toll-like receptor 2 SmithKline Beecham
Teicoplanin Anti-bacterial agents NPS Pharmaceuticals
Thymalfasin SDAAVDTSSEITTKDLKEKK SciClone Pharmaceuticals (SCLN)

perturbate and delocalize the membrane architecture high
hydrophobicity is required (Farkas etal. 2017).
Peng etal. (2017), synthesized four AMPs based on the
sequence of aa 113145 of LysAB2 and investigated the
modulations in antimicrobial potency while varying hydro-
phobicity level and cationic charge distribution. A peptide
variant, LysAB2 P3 (net charge: +6.0, hydrophobic ratio:
42%) displayed 16 folds higher antibacterial activity against
A. baumannii with very little haemolytic and no cytotoxic
activity against normal eukaryotic cells as compared to the
parent AMP LysAB2 (net charge: +4, hydrophobic ratio:
45%). Hence it can be speculated that optimized peptide
hydrophobicity and charge distribution promotes efficient
antimicrobial activity. Apart from hydrophobicity, the net
positive charge of an AMP is also essential for binding with
microbial membranes, thereby initiating peptide-membrane
interactions.
In a similar study by Yin etal. the authors detail that the
phenomenal difference in antimicrobial activity and toxic-
ity while altering hydrophobicity might be due to charge

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Table4Status of recently designed peptidomimetic molecules. Source: Data obtained from DRAMP database http://dramp.cpu-bioinfor.org/
browse/ClinicalTrialsData.php
Peptide Name Sequence
RDP58 (delmitide) H2N-D-Arg-D-Nle-D-Nle-D-Nle-D-
Arg-D-Nle-D-Nle-D-Nle-Gly-D-
Tyr-NH2
PMX-30063 (brilacidin)
Pexiganan acetate [MSI-78] GIGKFLKKAKKFGKAFVKILKK
Omiganan (CLS001) ILRWPWWPWRRK
OP-145 (24-mer peptide) IGKEFKRIVERIKRFLRELVRPLR
BL2060
AP-214
CD-NP
IMX942 KSRIVPAIPVSLL
Opebacan
XOMA-629
DiaPep277
neutralization effect. This happens because of dehydration
experienced by the membrane bound AMP, which results
in formation of -type aggregates at the membrane surface
and possibly leading to precipitation - thereby limiting the
peptide concentration impacting on the bacterial membrane,
and consequently reducing antimicrobial activity (Yin etal.
2012). Besides Hydrophobicity and cationic charge, the pep-
tide length is another critical factor determining the efficacy.
According to the BarrelStave model the AMPs penetrate
perpendicular into the membrane. Hence the length of an
AMP must be greater than or equivalent to the thickness
of the targets membrane (Yin etal. 2012; Yu etal. 2017).
Charge (Q) andPolar Angle ()
Despite the structural and compositional diversity, most of
the AMPs characterized till date possess an overall positive
charge ranging from +2 to +9 along with highly defined
cationic domain(s). Cationicity is certainly an important
factor for an initial electrostatic attraction of AMPs towards
the negatively charged head groups of the bacterial phos-
pholipid bilayer and other microorganisms. In bacteria, the
presence of acidic phospholipids (PG, PS, and CL) in the
cell membrane contributes for its net negative charge. Fur-
ther, the LPS and teichoic acid present in Gram-positive
13
International Journal of Peptide Research and Therapeutics
Stage of Development Description
Phase II (completed) Semisynthetic D-amino acid decapeptide derived
from HLA class I B2702
Phase II Defensin structural mimetic, non-peptide, small
molecule/copolymer
Phase III (faliure) Synthetic cationic host defense peptide(22-mer),
magainin derivative
Phase II Synthetic 12-mer cationic peptide derived from
indolicidin
Phase II (completed) Synthetic 24-mer peptide derived from LL-37 for
binding to lipopolysaccharides or lipoteichoic
acid
Lead optimization Synthetic compound comprising fatty acid and
lysine copolymers
Phase II (completed) Synthetic derivative from HDP -melanocyte-
stimulating hormone
Phase II Synthetic chimeric 37-mer derived from combi-
nation of two natriuretic peptides
Phase II Derivative of IDR-1 and indolicidin
Phase I/II Derivative of bactericidal/permeability-increasing
protein
Phase IIA 9-amino-acid peptide derivative of bactericidal/
permeability-increasing protein
Phase III HSP60 derivative (24-mer peptide) that induces T
regulatory cells
and Gram-negative bacterial membrane, contribute for an
additional negative charge. This results in nearly 50% greater
transmembrane electrical potential in prokaryotes in com-
parison with most mammalian cells (Wang etal. 2015; Liu
etal. 2015; Yeaman and Yount 2003).
The above-mentioned facts define the strong correlation
between peptide cationicity and antimicrobial activity, and
this has been validated in many studies. Studies with cati-
onicity enhanced analogues of the antimicrobial peptides
(AcrAP1 and AcrAP2), from the scorpion venom, exhib-
ited a broader spectrum of antimicrobial activity with an
enhanced potency. In contrast, the native peptides expressed
a narrow spectrum of activity with moderate potency. The
peptide analogues modified to improve biological potency
and spectrum of action surprisingly displayed growth modu-
lation effects on a variety of human cancer cell lines (Liu
etal. 2015; Yeaman and Yount 2003).
Polar angle is a measure of the relative proportion of
the polar and nonpolar facets present in an amphipathic
-helical peptide. This parameter enables to understand
the distribution of hydrophobic and hydrophilic amino
acid in a helical peptide. As an example, consider a
-helical peptide, which is exclusively composed of
hydrophobic amino acid residues on one side and the
other side solely composed of charged amino acids, then
International Journal of Peptide Research and Therapeutics

Table5List of latest peptides with their medical application. Source: Data obtained from DRAMP database http://dramp.cpu-bioinfor.org/
browse/ClinicalTrialsData.php
Peptide Name Sequence Developmental stage Medical Use

Colicin E1 (bacteriocin) Preclinical Gastrointestinal tract infections; Stomach

and intestine infections
Lactocin 160 (bacteriocin) Preclinical Urogenital tract infections; Bacterial
vaginosis
Bacteriocin OR-7 KTYYGTNGVHCTKNSLWGKVR- Preclinical Gastrointestinal tract infections; Campy-
LKNMKYDQNTTYMGRLQDILLG- lobacter infection
WATGAFGKTFH
Pediocin PA-1 (bacteriocin) KYYGNGVTCGKHSCSVDWG- Preclinical Gastrointestinal tract infections; Stomach
KATTCIINNGAMAWATGGHQGN- and intestine infections
HKC
Nisin A (Type A LANTIBIOTIC) ITSISLCTPGCKTGALMGCNMK- Preclinical Urogenital tract infections; Spermicidal
TATCHCSIHVSK activity
Bac8c RIWVIWRR Preclinical Staphylococus aureusanti-infectives
Temporin10a FLPLASLFSRLL Preclinical Staphylococus aureusanti-infectives
Syphaxin(SPX1-22) GVLDILKGAAKDLAGHVATKVINKI Phase I Staphylococus aureusanti-infectives
IDR-1002 VQRWLIVWRIRK Preclinical Staphylococus aureusanti-infectives
Buforin II TRSSRAGLQWPVGRVHRLLRK Preclinical Staphylococus aureusanti-infectives
SB006 (M6) QKKIRVRLSA Preclinical Gram-negative infections
IMX942 KSRIVPAIPVSLL Phase II Nosocomial infections, febrile, neutro-
penia
Ruminococcin C (bacteriocin) Preclinical Gastrointestinal tract infections; Stomach
and intestine infections (Rat model;
Invivo)
Planosporicin (bacteriocin) Preclinical Hospital-acquired infections; Multi-drug
resistant strain (Murine model; Invivo)
ESL5 Preclinical Gastrointestinal tract infections; Stomach
and intestine infections (Human model;
Invivo)

the polar angle will be 180 (Tseng etal. 2016). Further,
an imbalance between these proportions or a decrease
in the hydrophobic ratio in helix composition will pro-
portionately increase the polar angle and vice versa.
There is an inverse correlation between the polar angle
and membrane permeabilization capacity of the peptide
(Tseng etal. 2016; Duong etal. 2016). Usually, peptides
with narrow polar angles (having greater hydropho-
bic surface) can easily destabilize cell membrane lipid
structure and often require a smaller quantity of peptide
molecules and a large number of lipid molecules as com-
pared with peptides having a wide polar angle. The cor-
relation among polar angle, peptide stability and half-life
of peptide-induced membrane destabilization have also
been investigated and reported in many studies (Tian etal.
2016; Polanco 2013; Ebenhan etal. 2014). However, the
transmembrane pores induced by the smaller polar angles
peptides were less stable compared to those formed by
peptides with a wider polar angle (Kumar etal. 2016).
Challenges Involved inUse ofAMPs
asTherapeutics
Pharmaceutical and healthcare industries today, view
AMPs as a promising class of therapeutic molecules to
combat antimicrobial-resistant bacterial pathogens. The
remarkable development of peptide therapeutics in the last
decade led to a surprising number of marketing approv-
als in the year 2012 and has been reported that more than
100 peptide drug candidates were still in the pipeline
for approval. Peptides offer certain advantages as drugs;
which include high biological activity, specificity and low
levels of toxicity. However, challenges also exist for the
development and use of the peptide as therapeutics. Some
notable obstacles are; systemic route for administration,
stability, invivo kinetic parameters, toxicity, permeability
and so on (Hutchings etal. 2017).

13

The Right Peptide Form
The therapeutic efficacy of AMPs invivo is often over-
shadowed by their inability to reach the targets in an active
form. The physicochemical properties of a peptide greatly
influence its pharmacokinetic profile and metabolic fate
in the human system. Chemical degradation pathways for
peptides and proteins such as deamidation, racemization,
isomerization, hydrolysis, disulfide formation/exchange,
-elimination, and oxidation are the hindrances to over-
come (Manabe and Kawasaki 2017). Different strategies are
being developed and implemented to improve the stability
and functionality of peptide drugs. In specific, the suscep-
tibility of AMPs to proteases invivo is a major challenge
that limits their application in pharmaceutical industry. In
order to overcome this limitation, now the AMPs are being
synthesized as d-amino acids instead of l-amino acids,
which make the AMPs to withstand proteolytic degrada-
tion. Recently, Manabe and Kawasaki, have investigated
the antimicrobial properties of d and l-forms of sapesin
B (KLKLLLLLKLK-NH2). From the results, it has been
observed that d-form expressed higher antimicrobial activ-
ity against bacterial pathogens S. aureus and E. coli, relative
to its l-form. Moreover, it has also been noticed that the
elevated antimicrobial effect of d-form was not because of its
resistance against proteolytic degradation and instead due to
its membrane specific interactions made along with bacterial
cell surface components (Zhao etal. 2016). In another study
using Polybia-MPI a cationic peptide, the substitution with
d-lysines and the d-enantiomers for all of its l-lysines greatly
improved its stability against protease and a significant anti-
microbial activity was also observed in comparison to its
l-counterpart. Interestingly, the d-amino acid substitution
turned right-hand -helical conformation of the peptide to
left-hand conformation and also further decreased its hemo-
lytic activity (Afacan etal. 2012).
Manufacturing andCost Considerations
Though antimicrobial peptides are promising alternative to
traditional antibiotics, their utility is greatly limited due to
its high production costs involved, and thus the large-scale
production remains a challenge. To overcome this impedi-
ment, an effective strategy needs to be devised. The cost per
peptide could be minimized through adapting low-cost plat-
form technology and by bringing in improvements in process
strategies. Unfortunately, the current practice of solid-phase
peptide synthesis is prohibitively expensive and requires
expensive chemical precursor components during its large-
scale production. Although several approaches have been
proposed for industrial production of AMPs, till date, scale-
up has not been proven cost-effective. Even if production is
possible, further biochemical steps to facilitate purification
13
International Journal of Peptide Research and Therapeutics
are quite expensive and significantly reduce yield (Mar-
tin etal. 2015). In contrast to fluorenylmethoxycarbonyl
(FMOC) and other chemical syntheses of peptides, which
are complex and costly, recombinant platform offers cost-
effective approaches for the large-scale production. On the
other hand, the inherent complexity in using bacterial cell as
AMPs synthesizing factories has to be overcome (Zhao etal.
2015, New antimicrobial peptide kills strains resistant
to existing antibiotics 2016; Silva etal. 2016). Among the
recombinant studies reported for the production of AMPs in
microbial systems, E. coli host has been widely employed.
The major difficulties involved in the production of AMPs
in host systems include proteolytic degradation of peptides
and intrinsic antimicrobial activity exerted to the host sys-
tem by AMPs during its expression. At present, AMPs are
fused to protein carriers such as solubility enhancing carri-
ers, aggregation-promoting carriers, self-cleavable proteins
and signal secretion proteins. Thioredoxin and glutathione
transferase (GST), were the most frequently reported car-
rier proteins which account for more than one-third of all
reported fusion expressions. Whatever the technology might
be, all the methods need to rely on expensive chromatog-
raphy-based purification techniques to purify antimicrobial
peptides, which stands as a major setback in industrial scale
production of AMPs (Liu etal. 2017; Bommarius etal.
2010).
A number of researchers were attempting to address
these issues. Novozymes, a Danish biotech company, has
developed a novel antimicrobial peptide variant (Plectasin
NZ2114) which employs high-yield fungal expression sys-
tem for large-scale production of this peptide in a highly pure
state (Lee etal. 2016; Mathur etal. 2016). Recently, a mass
production strategy involving fusion protein technology was
studied for high yield production of certain antimicrobial
and immunomodulatory peptides (IDRs) including LL37,
CRAMP, and HHC-10. Here in this method, an intrinsic
cleavage system is utilized for freeing the pure peptide from
its fusion partner and in a simple two-step process, high
level of purification is achieved. The peptide was cleaved
from its fusion partner using a unique enzyme sumoase
(Premdjee and Payne 2017). Unlike classical chemical cleav-
age approaches such as Cyanogen bromide, which cleaves
C-terminally after methionine and hydrochloric acid based
cleavage of the acid-labile peptide bond between asparagi-
nes and proline (Schneider etal. 2010; Arenas etal. 2016).
Sumoase protease Ulp1 follows a unique mechanism by rec-
ognizing and specifically cleaving GlyGly residues after the
C-terminal present within SUMO, thereby releasing AMP
sequence, leaving no unwanted amino acids at the N-ter-
minus of the peptide. This may be a promising technology
for cost-effective industrial-scale production of AMPs and
IDRs (Bommarius etal. 2010; Premdjee and Payne 2017;
Mathur etal. 2016).
International Journal of Peptide Research and Therapeutics
In vivo Toxicity andStability
Therapeutic peptides are often characterized by their high
biological activity, high specificity and low toxicity (Less
accumulation in organs, Low or no hemolysis and drugdrug
interaction) (Gentilucci et al. 2010). Despite numerous
advantages, challenges include high production cost, low
storage stability and suboptimal invivo half-life (Jenssen
and Aspmo 2008).Metabolic stability of peptides is the
greatest obstacle faced on the way toward successful devel-
opment of bioactive peptides into therapeutic drugs in the
market. Methods are being developed to stabilize peptides
without reducing their effectiveness and affinity towards
the target molecule. Macrocyclic peptides or polycyclic
peptides are classical approaches to protect the peptides
against metabolism or to prolong their half-life. A variety
of other methods is still being explored and reported toward
protecting peptides against metabolism or to extend their
half-life. The approaches include derivatizing peptides with
carbohydrates (glycopeptides), incorporation of nonnatural
amino acids, which are not easily recognized by hydrolytic
enzymes and by introducing structural modifications to
sterically encumber the labile sites (Gentilucci etal. 2010;
Jenssen and Aspmo 2008). In recent days, a growing inter-
est in selective derivatizing of peptides with carbohydrates
has been observed, since glycosylation can confer superior
therapeutic efficacy, increased stability, higher aqueous solu-
bility, better bioavailability, enhanced target resolution and
longer invivo half-lives. Since toxicity being one of the bot-
tlenecks in peptide-based therapy, at present in silico models
are also being developed for predicting toxicity of peptides
and proteins.
A peptidomimetic is one of the leading and well-estab-
lished approaches in biotechnology and nanotechnology
which could be adapted for developing novel, effective non-
toxic therapeutic agents for performing specific operations
within a physiological environment (Gentilucci etal. 2010;
Ngambenjawong etal. 2016). Another major reason behind
peptide stability is rapid renal clearance, and this is also due
to protease degradation which results in low invivo bio-
availability, short half-life and limited access to intracellular
space. In case of synthetic peptides, conformational stabil-
ity is a debatable thing (Nordstrm and Malmsten 2017).
For successful development of peptide drugs, preliminary
screening assays are most important and essential for the
elimination of unstable peptides entering into drug devel-
opment pipeline, which considerably affects the production
cost and efficiency. Stability of peptide in serum can be
determined using techniques such as reverse phasehigh-
performance liquid chromatography (RP-HPLC) and mass
spectroscopy (MS) approach for both invitro and invivo
(Ngambenjawong etal. 2016; Nordstrm and Malmsten
2017; Weinstock etal. 2012).
Incorporation of unnaturalamino acids, peptide trunca-
tiona and inducing chemical modifications could be some
of the possible ways to reduce invivo toxicity and improve
invivo peptide stability. Koh et al., has demonstrated
enhanced antimicrobial activity and stability upon intro-
ducing lipid modification. It should also be noted that the
modification should not disturb the cationic and hydropho-
bic balance (Li etal. 2017; Koh etal. 2015). Recently a
new class of peptidomimetics termed AApeptides, which
are oligomers of N-Acylated-N-Aminoethyl amino acid has
been developed which mimic the action of Host defense pep-
tides capable of inhibiting the growth of multidrug resistant
Gram-positive and Gram-negative bacteria. These peptides
are protease resistant since it has been built on non-natural
structural backbone. -AApeptides and -AApeptides are
two major sub-types of AApeptides (Sang etal. 2017).
Delivery Platforms: Barriers andChallenges
Delivery systems play a vital role in the development of
potent and safe AMP-based therapeutic drugs. The major
objectives of delivery systems designed for peptide thera-
peutics include (i) Preservation of chemical or biological
activity of AMPs either in the formulation or after admin-
istration, (ii) Reduced toxicity and adverse side effects, (iii)
sustained and or controlled release rate of AMPs, (iv) pro-
mote biofilm penetration, or co-localization with intracel-
lular pathogens (Kovalainen etal. 2015; Thota etal. 2016).
In recent years, a variety of advancements has been made in
peptide drug delivery through active or passive transporters,
carriers, transdermal and nasal delivery systems. At present,
peptides are parenterally delivered (via injection), since oral
administration leads to inactivation and degradation in the
digestive tract. The other obstacles include short half-life,
lower penetration capacity and targeted delivery (Elofsson
etal. 2015). Various nanoformulation platforms for targeted
peptide delivery, controlled and or sustained-release strate-
gies and technologies offering proteolytic stability are being
investigated (Lee and Lee 2015; Widenbring etal. 2014;
Muheem et al. 2016). Microgels and related polymeric
systems offer exciting opportunities for delivery of AMPs
and low-Mw drugs (Fosgerau and Hoffmann 2015). Fur-
thermore, from industrial perspective, design simplicity,
robustness, and scale-up approaches are likely to be the key
for any peptide delivery systems (Kovalainen etal. 2015;
Ghosh 2016).
Global Market forTherapeutic peptides
Over the past decade, therapeutic peptides have gained a
wide range of applications in the fields of healthcare and
Biopharmaceuticals. Furthermore, in recent days the
13

research on therapeutic peptide is undergoing a renaissance
for commercial reasons. Novel strategies in peptide design
have propelled a wave of peptide therapeutics in market and
research. Currently, an approximate of 140 therapeutic pep-
tides are in clinical trials, and over 500 were in preclinical
development (Fosgerau and Hoffmann 2015). The commer-
cial market for novel peptide therapeutics was estimated to
be $17.50billion in 2015. The healthcare expenditure in two
of the fastest growing economies namely Brazil and India
went up by 0.3 and 0.2% 2014 over 2013 respectively, which
is a key economic factor driving the global peptide thera-
peutics market (Bahar and Ren 2013). According to a recent
report on worldwide peptide market Peptide Therapeutics
Market: Global Industry Analysis and Opportunity Assess-
ment, 20152025, published by Future Market Insights
market intelligence and consulting firm, the global peptide
therapeutics market is projected to rise over 10% CAGR
during 20152025.
Conclusion
The rapid emergence of MDR pathogens has necessitated an
urgent need to develop novel antimicrobials. As biological
anti-infective agents, AMPs can be directly antimicrobial
and immunomodulatory. It has been predicted that 10mil-
lion people per year will be killed by 2050 globally, causing
$100 trillion loss to the global economy (Silva etal. 2016).
AMPs are less likely to promote microbial resistance since
they interfere with multiple biological processes in a patho-
gen or modulate the host immune system rather than target-
ing the pathogen (Narayana and Chen 2015). Furthermore,
AMPs are capable of suppressing harmful inflammatory
responses associated with the infection caused. Peptides
hold high selectivity and efficiency and, at the same time,
relatively safe and well tolerated (Aoki and Ueda 2013).
These properties make AMPs an attractive alternative in the
treatment of MDR infections. So far thousands of natural
and synthetic AMPs have been identified, reported and still
being developed, but only a few of them have reached clini-
cal trials successfully (Aoki and Ueda 2013). Recently, new
antimicrobial peptide Clavanin-MO has been developed by
a team of researchers at MIT, University of Brasilia, and the
University of British Columbia against multidrug resistant
Escherichia coli and Staphylococcus aureus. This peptide is
a synthetic derivative from parent peptide Clavanin-A with
improved hydrophobicity. This novel peptide was found to
suppress sepsis by stimulating production of immune media-
tors GM-CSF, IFN- and MCP-1, thereby increasing anti-
inflammatory cytokine (IL-10) synthesis and repressing
the levels of pro-inflammatory cytokine (IL-12 and TNF-
). This peptide also holdsa potentiant to cure infections
caused by Pseudomonas aeruginosa, which is a causative
13
International Journal of Peptide Research and Therapeutics
agent for most biofilm infections and often affect the lungs
of cystic fibrosis patients (105, Silva etal. 2016). In order
to design and develop novel antimicrobials with desired
potency and efficiency, a deeper understanding and knowl-
edge over structure-activity-propertybehavior relationship
and relating them all together is a critical requirement for
development of novel therapeutics. Riduan and co has devel-
oped a novel class of antimicrobial imidazolium oligomers
capable of ultrafast killing (>99.7% killing within 30s), and
possess superior activity, excellent selectivity, self-gelling
properties. The Molecular dynamic simulations studies have
reavealed that ultra fast killing is due to spontaneous pene-
tration and translocation across the microbial cell membrane
within a very short timescale of seconds to minutes (Riduan
etal. 2016).
Issues regarding manufacturing cost, peptide stability,
and toxicity were some of the major challenges not yet been
completely addressed. Although more work is needed, sub-
stantial strides have been made in the recent years to over-
come these setbacks, and the future looks promising for the
development and widespread use of peptides as therapeutics
targeting MDR pathogens. More focus is to be made on syn-
thetic or peptides mimicking natural antibiotics. Since they
rarely develop resistance, this could be a possible way to
fight with multi-drug resistant organisms. Only when these
aspects have been unraveled in greater detail, the AMP-
based therapeutics can likely to be able to reach their full
potential. Above all, the best way to combat against anti-
microbial resistance (AMR) is by prevention. An holistic
and collaborative approach towards prevention and contain-
ment of AMR across all nations, government and society is
required to minimize the emergence and spread of antimi-
crobial resistance. Further efforts for enhancing awareness,
strengthening AMR surveillance, educating people about
responsible use of antibiotics, reducing infections and pro-
moting research globally is also required.
Acknowledgements The authors wish to thank SERB and UGC,
Government of India, for financial support through major project. A
special thanks to Prof. Dr. K. Ruckmani, Head and Director, Depart-
ment of Pharmaceutical Technology, Centre for. Excellence in Nanobio
Translational REsearch. (CENTRE), University College of Engineer-
ing, Bharathidasan Institute of Technology Campus, Anna University,
Tiruchirappalli-620024, Tamil Nadu, India for her constant support.
Funding This study was supported by Science and Engineering
research board, Department of Science and Technology under the
scheme of Empowerment and Equity Opportunities for Excellence in
Science. Sanction Order No: SB/EMEQ-034/2014 dated 06.07.2015.
University Grants Commission, National Fellowship for SC, Award
Letter No.: F1-17.1/2017-18/RGNF-2017-18-SC-TAM-45554. Dated:
16/08/2017.
Compliance with Ethical Standards
Conflict of interest Authors declare no conflict of interest.
International Journal of Peptide Research and Therapeutics
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
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