Antibiotics and their sources

Chloramphenicol
Polymyxins
Vancomycin
Daptomycin
Bacitracin
Cycloserine
Erythromycin
Lincomycin
Streptomycin
Gentamicin
Rifamycin
Capreomycin
Amphotericin
Griseofulvin
Mupirocin

Streptomyces venezuelae
Bacillus polymyxa
Streptococcus orientalis
Streptomyces roseosporus
Bacillus subtilis
Streptomyces orchidaceus
Streptomyces erythreus
Streptomyces lincolnensis
Streptomyces griseus
Micromonospora purpurea
Streptomyces mediterranei
Streptomyces capreolus
Streptomyces nodosus
Penicillium spp.
Pseudomonas fluorescens

Mechanism of Action of Antimicrobial Agents

-lactam
antibiotics

Vancomycin

-lactam antibiotics, inhibit bacterial growth by interfering with the

transpeptidation reaction of bacterial cell wall synthesis. The cell wall is
composed of a complex cross-linked polymer of polysaccharides and
polypeptides, peptidoglycan (murein, mucopeptide). The polysaccharide
contains alternating amino sugars, N-acetylglucosamine and Nacetylmuramic acid. A five-amino-acid peptide is linked to the Nacetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine.
Penicillin-binding protein (PBP, an enzyme) removes the terminal alanine
in the process of forming a cross-link with a nearby peptide. Cross-links
give the cell wall its structural rigidity. -Lactam antibiotics, structural
analogs of the natural D-Ala-D-Ala substrate, covalently bind to the active
site of PBPs. This inhibits the transpeptidation reaction (Figure), halting
peptidoglycan synthesis, and the cell dies. The exact mechanism of cell
death is not completely understood, but autolysins and disruption of cell
wall morphogenesis are involved. Penicillins and cephalosporins kill
bacterial cells only when they are actively growing and synthesizing cell
wall.
inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus of
nascent peptidoglycan pentapeptide. This inhibits the transglycosylase,
preventing further elongation of peptidoglycan and cross-linking. The

peptidoglycan is thus weakened, and the cell becomes susceptible to

lysis. The cell membrane is also damaged, which contributes to the
antibacterial effect
Teicoplanin
Daptomycin

Similar to vancomycin
The precise mechanism of action is not known, but it appears to bind to
and depolarize the cell membrane, causing potassium efflux and rapid
cell death

Fosfomycin
trometamol

It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently

binding to the cysteine residue of the active site and blocking the addition
of phosphoenolpyruvate to UDP-N-acetylglucosamine. This reaction is
the first step in the formation of UDP-N-acetylmuramic acid, the
precursor of N-acetylmuramic acid, which is found only in bacterial cell
walls. The drug is transported into the bacterial cell by glycerophosphate
or glucose 6-phosphate transport systems. Resistance is due to
inadequate transport of drug into the cell

Bacitracin

inhibits cell wall formation by interfering with dephosphorylation in cycling

of the lipid carrier that transfers peptidoglycan subunits to the growing
cell wall

Cycloserine

Cycloserine is a structural analog of D-alanine and inhibits the

incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting
alanine racemase, which converts L-alanine to D-alanine, and D-alanylD-alanine ligase

TETRACYCLINES
Tetracyclines
Tetracyclines enter microorganisms in part by passive diffusion and in
part by an energy-dependent process of active transport. Susceptible
cells concentrate the drug intracellularly. Once inside the cell,
tetracyclines bind reversibly to the 30S subunit of the bacterial ribosome,
blocking the binding of aminoacyl-tRNA to the acceptor site on the
mRNA-ribosome complex . This prevents addition of amino acids to the
growing peptide.
MACROLIDES
Erythromycin

Clarithromycin
Azithromycin

Inhibition of protein synthesis occurs via binding to the 50S ribosomal

RNA, which blocks the aminoacyl translocation reaction and formation of
initiation complexes
Similar to erythromycin
Similar to erythromycin

KETOLIDES
Telithromycin

Similar to erythromycin

LINCOSAMIDES
Clindamycin
Clindamycin, like erythromycin, inhibits protein synthesis by interfering
with the formation of initiation complexes and with aminoacyl
translocation reactions. The binding site for clindamycin on the 50S
subunit of the bacterial ribosome is identical with that for erythromycin.

CHLORAMPHENICOL
Chloramphenicol potent inhibitor of microbial protein synthesis. It binds reversibly to the
50S subunit of the bacterial ribosome and inhibits the peptidyl
transferase step of protein synthesis. H influenzae, N meningitidis, and
some strains of bacteroides are highly susceptible, and for them
chloramphenicol may be bactericidal.
STREPTOGRAMINS
QuinupristinSimilar to macrolides (MLS-B site)
dalfopristin

OXAZOLIDINONES
inhibits protein synthesis by preventing formation of the ribosome
Linezolid
complex that initiates protein synthesis. Its unique binding site, located
on 23S ribosomal RNA of the 50S subunit, results in no cross-resistance
with other drug classes.

AMINOGLYCOSIDES
Streptomycin,
Neomycin,
Kanamycin,
Amikacin,
Gentamicin,
Tobramycin,
Sisomicin,
Netilmicin

Aminoglycosides are irreversible inhibitors of protein synthesis, but the

precise mechanism for bactericidal activity is not known. The initial event
is passive diffusion via porin channels across the outer membrane. Drug
is then actively transported across the cell membrane into the cytoplasm
by an oxygen-dependent process. Inside the cell, aminoglycosides bind
to specific 30S-subunit ribosomal proteins (S12 in the case of
streptomycin). Protein synthesis is inhibited by aminoglycosides in at
least three ways : (1) interference with the initiation complex of peptide
formation; (2) misreading of mRNA, which causes incorporation of
incorrect amino acids into the peptide, resulting in a nonfunctional or
toxic protein; and (3) breakup of polysomes into nonfunctional
monosomes.

Spectinomycin

Spectinomycin is an aminocyclitol antibiotic that is structurally related to

aminoglycosides. It lacks amino sugars and glycosidic bonds.MOA
similar to aminoglycosides.

Sulfonamides-Trimethamine-Pyrimethamine
Sulfonamides
Trimethoprim

Pyrimethamine

sulfonamides are structural analogs of PABA, they inhibit

dihydropteroate synthase and folate production.
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterial
dihydrofolic acid reductase, which converts dihydrofolic acid to
tetrahydrofolic acid, a step leading to the synthesis of purines and
ultimately to DNA
Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolic
acid reductase of protozoa compared with that of mammalian cells

Quonolones and Fluoroquinolones

Quinolones
(Nalidixic acid)
and
Fluoroquinolones
(Ciprofloxacin
Gatifloxacin
Gemifloxacin
Levofloxacin
Lomefloxacin
Moxifloxacin
Norfloxacin
Ofloxacin)

Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II

(DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase prevents
the relaxation of positively supercoiled DNA that is required for normal
transcription and replication. Inhibition of topoisomerase IV interferes
with separation of replicated chromosomal DNA into the respective
daughter cells during cell division.

ANTIMYCOBACTERIAL DRUGS
Isoniazid
Isoniazid inhibits synthesis of mycolic acids, which are essential
components of mycobacterial cell walls. Isoniazid is a prodrug that is
activated by KatG, the mycobacterial catalase-peroxidase. The activated
form of isoniazid forms a covalent complex with an acyl carrier protein
(AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which
blocks mycolic acid synthesis and kills the cell.
Rifampin
Rifampin binds to the subunit of bacterial DNA-dependent RNA
polymerase and thereby inhibits RNA synthesis. Resistance results from
any one of several possible point mutations in rpoB, the gene for the
subunit of RNA polymerase. These mutations result in reduced binding
of rifampin to RNA polymerase. Human RNA polymerase does not bind
rifampin and is not inhibited by it. Rifampin is bactericidal for
mycobacteria.
Ethambutol
Ethambutol inhibits mycobacterial arabinosyl transferases, which are
encoded by the embCAB operon. Arabinosyl transferases are involved in
the polymerization reaction of arabinoglycan, an essential component of
the mycobacterial cell wall. Resistance to ethambutol is due to mutations
resulting in overexpression of emb gene products or within the embB
structural gene.
Pyrazinamide
Pyrazinamide is converted to pyrazinoic acidthe active form of the
drugby mycobacterial pyrazinamidase, which is encoded by pncA. The
drug target and mechanism of action are unknown. Resistance may be
due to impaired uptake of pyrazinamide or mutations in pncA that impair
conversion of pyrazinamide to its active form.
Streptomycin

See in Aminoglycoside section.

Second line drugs

Ethionamide
Ethionamide is chemically related to isoniazid and also blocks the
synthesis of mycolic acids.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor.
Cycloserine
inhibitor of cell wall synthesis. Discussed above.
Paraaminosalicylic folate synthesis antagonist that is active almost exclusively against M
acid(PAS)
tuberculosis
Kanamycin&
Discussed above.
Amikacin
Ciprofloxacin,
Discussed above.
Levofloxacin,
Gatifloxacin, And
Moxifloxacin
Linezolid
Discussed above.
Rifabutin
Similar to Rifampicin.
Rifapentine
Similar to Rifampicin.
Anti-leprosy drugs
Dapsone(diamino
Discussed above
diphenylsulfone),
Rifampicin
Clofazimine
Clofazimine is a phenazine dye. Its mechanism of action is unknown
but may involve DNA binding.

Antifungal agents
Amphotericin B
Amphotericin B is selective in its fungicidal effect because it exploits the
difference in lipid composition of fungal and mammalian cell membranes.
Ergosterol, a cell membrane sterol, is found in the cell membrane of
fungi, whereas the predominant sterol of bacteria and human cells is
cholesterol. Amphotericin B binds to ergosterol and alters the
permeability of the cell by forming amphotericin B-associated pores in
the cell membrane. As suggested by its chemistry, amphotericin B
combines avidly with lipids (ergosterol) along the double bond-rich side
of its structure and associates with water molecules along the hydroxylrich side. This amphipathic characteristic facilitates pore formation by
multiple amphotericin molecules, with the lipophilic portions around the
outside of the pore and the hydrophilic regions lining the inside. The pore
allows the leakage of intracellular ions and macromolecules, eventually
leading to cell death. Some binding to human membrane sterols does
occur, probably accounting for the drug's prominent toxicity
Flucytosine

Flucytosine is taken up by fungal cells via the enzyme cytosine

permease. It is converted intracellularly first to 5-FU and then to 5fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and RNA synthesis,
respectively. Human cells are unable to convert the parent drug to its
active metabolites.

Azoles
Azoles are synthetic compounds that can be classified as either imidazoles or triazoles. The
imidazoles consist of ketoconazole, miconazole, and clotrimazole . The triazoles include
itraconazole, fluconazole, and voriconazole.
Azoles
The antifungal activity of azole drugs results from the reduction of
ergosterol synthesis by inhibition of fungal cytochrome P450 enzymes.
The specificity of azole drugs results from their greater affinity for fungal
than for human cytochrome P450 enzymes.
Echinocandins
Caspofungin,
micafungin, and
anidulafungin

Griseofulvin

Terbinafine

Nystatin

Echinocandins act at the level of the fungal cell wall by inhibiting the
synthesis of (13) glucan. This results in disruption of the fungal cell
wall and cell death.

Griseofulvin's mechanism of action at the cellular level is unclear, but it

is deposited in newly forming skin where it binds to keratin, protecting
the skin from new infection
Like griseofulvin, terbinafine is a keratophilic medication, but unlike
griseofulvin, it is fungicidal. Like the azole drugs, it interferes with
ergosterol biosynthesis, but rather than interacting with the P450
system, terbinafine inhibits the fungal enzyme squalene epoxidase.
This leads to the accumulation of the sterol squalene, which is toxic to
the organism.
Nystatin is a polyene macrolide much like amphotericin B.

Antiviral drugs

Agents To Treat Herpes Simplex Virus (HSV) & Varicella-Zoster Virus (VZV) Infections
Acyclovir

Acyclovir requires three phosphorylation steps for activation. It is

converted first to the monophosphate derivative by the virus-specified
thymidine kinase and then to the di- and triphosphate compounds by host
cell enzymes . Because it requires the viral kinase for initial
phosphorylation, acyclovir is selectively activated, and the active
metabolite accumulates, only in infected cells. Acyclovir triphosphate
inhibits viral DNA synthesis by two mechanisms: competition with
deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA
template as an irreversible complex; and chain termination following
incorporation into the viral DNA.

Valacyclovir

Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted to

acyclovir after oral administration via intestinal and hepatic first-pass
metabolism

Famciclovir

Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, After oral

administration, famciclovir is rapidly converted by first-pass metabolism to
penciclovir. As with acyclovir, activation by phosphorylation is catalyzed
by the virus-specified thymidine kinase in infected cells, followed by
competitive inhibition of the viral DNA polymerase to block DNA
synthesis. Unlike acyclovir, however, penciclovir does not cause chain
termination. Penciclovir triphosphate has lower affinity for the viral DNA

polymerase than acyclovir triphosphate, but it achieves higher

intracellular concentrations and has a more prolonged intracellular effect
in experimental systems.
Docosanol

Docosanol is a saturated 22-carbon aliphatic alcohol that inhibits fusion

between the plasma membrane and the HSV envelope, thereby
preventing viral entry into cells and subsequent viral replication.

Trifluridine

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that

inhibits viral DNA synthesis. It is phosphorylated intracellularly to its active
form by host cell enzymes, and then competes with thymidine
triphosphate for incorporation by the viral DNA polymerase. Incorporation
of trifluridine triphosphate into both viral and host DNA prevents its
systemic use.

Agents To Treat CytoMegaloVirus (CMV) Infections

Ganciclovir

Valganciclovir

Foscarnet
(phosphonofor
mic acid)
Cidofovir

Ganciclovir is an acyclic guanosine analog that requires activation by

triphosphorylation before inhibiting the viral DNA polymerase. Initial
phosphorylation is catalyzed by the virus-specified protein kinase
phosphotransferase UL97 in CMV-infected cells. The activated compound
competitively inhibits viral DNA polymerase and causes termination of viral
DNA elongation
Valganciclovir is an L-valyl ester prodrug of ganciclovir that exists as a
mixture of two diastereomers. After oral administration, both diastereomers
are rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases.
Foscarnet is an inorganic pyrophosphate compound that inhibits viral DNA
polymerase, RNA polymerase, and HIV reverse transcriptase directly
without requiring activation by phosphorylation.
In contrast to ganciclovir, phosphorylation of cidofovir to the active
diphosphate is independent of viral enzymes. After phosphorylation,
cidofovir acts both as a potent inhibitor of and as an alternative substrate
for viral DNA polymerase, competitively inhibiting DNA synthesis and
becoming incorporated into the viral DNA chain.

Antiretroviral drugs

Nucleoside & Nucleotide Reverse Transcriptase Inhibitors

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can also
be incorporated into the growing viral DNA chain to cause termination. Each requires
intracytoplasmic activation via phosphorylation by cellular enzymes to the triphosphate form.
Most have activity against HIV-2 as well as HIV-1.
Nonnucleoside Reverse Transcriptase Inhibitors
The NNRTIs bind directly to HIV-1 reverse transcriptase, resulting in blockade of
RNA- and DNA-dependent DNA polymerase. The binding site of NNRTIs is near to but
distinct from that of NRTIs. Unlike the NRTI agents, NNRTIs neither compete with
nucleoside triphosphates nor require phosphorylation to be active.

Protease Inhibitors
During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene products
are translated into polyproteins, and these become immature budding particles. Protease is
responsible for cleaving these precursor molecules to produce the final structural proteins of
the mature virion core. By preventing cleavage of the Gag-Pol polyprotein, protease
inhibitors (PIs) result in the production of immature, noninfectious viral particles
Fusion Inhibitors
Enfuvirtide (formerly called T-20) is the first representative of a new class of
antiretroviral agents: It is a fusion inhibitor that blocks entry into the cell . Enfuvirtide, a
synthetic 36-amino-acid peptide, binds to the gp41 subunit of the viral envelope glycoprotein,
preventing the conformational changes required for the fusion of the viral and cellular
membranes.

ANTIHEPATITIS AGENTS
Interferon Alfa

Interferons are host cytokines that exert complex antiviral,

immunomodulatory, and antiproliferative activities (see Chapter 56).
Interferon (IFN)-alfa appears to function by induction of intracellular
signals following binding to specific cell membrane receptors, resulting in
inhibition of viral penetration, translation, transcription, protein
processing, maturation, and release, as well as increased expression of
major histocompatibility complex antigens, enhanced phagocytic activity
of macrophages, and augmentation of the proliferation and survival of
cytotoxic T cells.

Adefovir dipivoxil Adefovir dipivoxil is the diester prodrug of adefovir, an acyclic

phosphonated adenine nucleotide analog. It is phosphorylated by cellular
kinases to the active diphosphate metabolite and then competitively
inhibits HBV DNA polymerase to result in chain termination after
incorporation into the viral DNA.

Entecavir

Ribavirin

Entecavir is an orally administered guanosine nucleoside analog (Figure

492) that competitively inhibits all three functions of HBV DNA
polymerase, including base priming, reverse transcription of the negative
strand, and synthesis of the positive strand of HBV DNA.
Ribavirin is a guanosine analog that is phosphorylated intracellularly by
host cell enzymes. Although its mechanism of action has not been fully
elucidated, it appears to interfere with the synthesis of guanosine
triphosphate, to inhibit capping of viral messenger RNA, and to inhibit the
viral RNA-dependent polymerase of certain viruses.

ANTI-INFLUENZA AGENTS
Amantadine & Amantadine (1-aminoadamantane hydrochloride) and its -methyl
Rimantadine
derivative, rimantadine, are cyclic amines of the adamantine family that
block the M2 proton ion channel of the virus particle and inhibit uncoating
of the viral RNA within infected host cells, thus preventing its replication.
They are active against influenza A only.
Zanamivir
& The neuraminidase inhibitors zanamivir and oseltamivir, analogs of sialic
acid, interfere with release of progeny influenza virus from infected to new
Oseltamivir
host cells, thus halting the spread of infection within the respiratory tract.
Unlike amantadine and rimantadine, zanamivir and oseltamivir have
activity against both influenza A and influenza B viruses.

Palivizumab
Imiquimod

Palivizumab is a humanized monoclonal antibody directed against an

epitope in the A antigen site on the F surface protein of RSV.
Imiquimod is an immune response modifier. The mechanism of action
against the human papillomavirus (HPV)-induced lesions is unknown.

METRONIDAZOLE, MUPIROCIN, POLYMYXINS

Metronidazole
Tinidazole

The nitro group of metronidazole is chemically reduced in anaerobic

bacteria and sensitive protozoans. Reactive reduction products appear
to be responsible for antimicrobial activity.

Mupirocin

Mupirocin (pseudomonic acid) inhibits staphylococcal isoleucyl tRNA

synthetase.

Polymyxin B &
Polymyxin
E(Colistin)

Polymyxins act like cationic detergents. They attach to and disrupt

bacterial cell membranes. They also bind and inactivate endotoxin.

URINARY ANTISEPTICS
Nitrofurantoin
Methenamine

Below pH 5.5, methenamine releases formaldehyde, which is

antibacterial.

ANTIMALARIALS
Chloroquine
Chloroquine probably acts by concentrating in parasite food vacuoles,
Amodiaquine
preventing the polymerization of the hemoglobin breakdown product,
heme, into hemozoin, and thus eliciting parasite toxicity due to the
buildup of free heme.
Quinine, quinidine
Mefloquine
Primaquine
Halofantrine
Lumefantrine
Atovaquone

Unknown

The mechanism of action of atovaquone is uncertain. In plasmodia it

appears to disrupt mitochondrial electron transport.
selectively inhibit plasmodial dihydrofolate reductase

Pyrimethamine
and proguanil
Sulfonamides and inhibit another enzyme in the folate pathway, dihydropteroate synthase
sulfones
Artemisinin
The antimalarial activity of artemisinins may result from the production
of free radicals that follows the iron-catalyzed cleavage of the
artemisinin endoperoxide bridge in the parasite food vacuole or from
inhibition of a parasite calcium ATPase.
ANTI-HELMINTHICS
Albendazole
Benzimidazoles are thought to act against nematodes by inhibiting
Mebendazole
microtubule synthesis.
DEC
Diethylcarbamazine immobilizes microfilariae and alters their surface
structure, displacing them from tissues and making them more
susceptible to destruction by host defense mechanisms. The mode of
action against adult worms is unknown.
Ivermectin

Metrifonate
(Trichlorfon)

Niclosamide

Ivermectin appears to paralyze nematodes and arthropods by

intensifying -aminobutyric acid (GABA)-mediated transmission of
signals in peripheral nerves.
Metrifonate, an organophosphate compound. The mode of action is
thought to be related to cholinesterase inhibition. This inhibition
temporarily paralyzes the adult worms, resulting in their shift from the
bladder venous plexus to small arterioles of the lungs, where they are
trapped, encased by the immune system, and die.
Adult worms (but not ova) are rapidly killed, presumably due to
inhibition of oxidative phosphorylation or stimulation of ATPase activity.

Piperazine

Piperazine causes paralysis of ascaris by blocking acetylcholine at the

myoneural junction; unable to maintain their position in the host, live
worms are expelled by normal peristalsis.

Praziquantel

Praziquantel appears to increase the permeability of trematode and

cestode cell membranes to calcium, resulting in paralysis,
dislodgement, and death.

Pyrantel

neuromuscular blocking agent that causes release of acetylcholine and

inhibition of cholinesterase; this results in paralysis, which is followed by
expulsion of worms.