MOA Antibiotics

8/10/2019 MOA Antibiotics

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Antibiotics and their sources

Chloramphenicol Streptomyces venezuelaePolymyxins Bacillus polymyxaVancomycin Streptococcus orientalisDaptomycin Streptomyces roseosporusBacitracin Bacillus subtilis Cycloserine Streptomyces orchidaceusErythromycin Streptomyces erythreusLincomycin Streptomyces lincolnensisStreptomycin Streptomyces griseusGentamicin Micromonospora purpureaRifamycin Streptomyces mediterraneiCapreomycin Streptomyces capreolus

Amphotericin Streptomyces nodosusGriseofulvin Penicillium spp.Mupirocin Pseudomonas fluorescens


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Mechanism of Action of Antimicrobial Agents

-lactamantibiotics

-lactam antibiotics, inhibit bacterial growth by interfering with thetranspeptidation reaction of bacterial cell wall synthesis. The cell wall iscomposed of a complex cross-linked polymer of polysaccharides andpolypeptides, peptidoglycan (murein, mucopeptide). The polysaccharidecontains alternating amino sugars, N-acetylglucosamine and N-acetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine.Penicillin-binding protein (PBP, an enzyme) removes the terminal alaninein the process of forming a cross-link with a nearby peptide. Cross-linksgive the cell wall its structural rigidity. -Lactam antibiotics, structuralanalogs of the natural D-Ala-D-Ala substrate, covalently bind to the activesite of PBPs. This inhibits the transpeptidation reaction (Figure), haltingpeptidoglycan synthesis, and the cell dies. The exact mechanism of celldeath is not completely understood, but autolysins and disruption of cellwall morphogenesis are involved. Penicillins and cephalosporins killbacterial cells only when they are actively growing and synthesizing cellwall.

Vancomycin inhibits cell wall synthesis by binding firmly to the D-Ala-D-Ala terminus ofnascent peptidoglycan pentapeptide. This inhibits the transglycosylase,preventing further elongation of peptidoglycan and cross-linking. The


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peptidoglycan is thus weakened, and the cell becomes susceptible tolysis. The cell membrane is also damaged, which contributes to theantibacterial effect

Teicoplanin Similar to vancomycin

Daptomycin The precise mechanism of action is not known, but it appears to bind toand depolarize the cell membrane, causing potassium efflux and rapidcell death

Fosfomycintrometamol

It inhibits the cytoplasmic enzyme enolpyruvate transferase by covalentlybinding to the cysteine residue of the active site and blocking the additionof phosphoenolpyruvate to UDP- N -acetylglucosamine. This reaction isthe first step in the formation of UDP- N-acetylmuramic acid, theprecursor of N-acetylmuramic acid, which is found only in bacterial cellwalls. The drug is transported into the bacterial cell by glycerophosphateor glucose 6-phosphate transport systems. Resistance is due toinadequate transport of drug into the cell

Bacitracin inhibits cell wall formation by interfering with dephosphorylation in cyclingof the lipid carrier that transfers peptidoglycan subunits to the growingcell wall

Cycloserine Cycloserine is a structural analog of D-alanine and inhibits theincorporation of D-alanine into peptidoglycan pentapeptide by inhibitingalanine racemase, which converts L-alanine to D-alanine, and D-alanyl-D-alanine ligase

TETRACYCLINES Tetracyclines Tetracyclines enter microorganisms in part by passive diffusion and in

part by an energy-dependent process of active transport. Susceptiblecells 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 themRNA-ribosome complex . This prevents addition of amino acids to thegrowing peptide.

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

RNA, which blocks the aminoacyl translocation reaction and formation of

initiation complexes Clarithromycin Similar to erythromycin Azithromycin Similar to erythromycin

KETOLIDES Telithromycin Similar to erythromycin

LINCOSAMIDESClindamycin Clindamycin, like erythromycin, inhibits protein synthesis by interfering

with the formation of initiation complexes and with aminoacyltranslocation reactions. The binding site for clindamycin on the 50Ssubunit of the bacterial ribosome is identical with that for erythromycin.


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CHLORAMPHENICOL Chloramphenicol potent inhibitor of microbial protein synthesis. It binds reversibly to the

50S subunit of the bacterial ribosome and inhibits the peptidyltransferase step of protein synthesis. H influenzae, N meningitidis, andsome strains of bacteroides are highly susceptible, and for them

chloramphenicol may be bactericidal. STREPTOGRAMINS Quinupristin-dalfopristin

Similar to macrolides (MLS-B site)

OXAZOLIDINONES

Linezolid inhibits protein synthesis by preventing formation of the ribosomecomplex that initiates protein synthesis. Its unique binding site, locatedon 23S ribosomal RNA of the 50S subunit, results in no cross-resistancewith other drug classes.

AMINOGLYCOSIDES

Streptomycin,Neomycin,Kanamycin,

Amikacin,Gentamicin,Tobramycin,Sisomicin,Netilmicin

Aminoglycosides are irreversible inhibitors of protein synthesis, but theprecise mechanism for bactericidal activity is not known. The initial eventis passive diffusion via porin channels across the outer membrane. Drugis then actively transported across the cell membrane into the cytoplasmby an oxygen-dependent process. Inside the cell, aminoglycosides bindto specific 30S-subunit ribosomal proteins (S12 in the case ofstreptomycin). Protein synthesis is inhibited by aminoglycosides in atleast three ways : (1) interference with the initiation complex of peptideformation; (2) misreading of mRNA, which causes incorporation ofincorrect amino acids into the peptide, resulting in a nonfunctional ortoxic protein; and (3) breakup of polysomes into nonfunctionalmonosomes.


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Spectinomycin Spectinomycin is an aminocyclitol antibiotic that is structurally related toaminoglycosides. It lacks amino sugars and glycosidic bonds. MOAsimilar to aminoglycosides.

Sulfonamides-Trimethamine-Pyrimethamine

Sulfonamides sulfonamides are structural analogs of PABA, they inhibitdihydropteroate synthase and folate production.

Trimethoprim Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhibits bacterialdihydrofolic acid reductase, which converts dihydrofolic acid totetrahydrofolic acid, a step leading to the synthesis of purines andultimately to DNA

Pyrimethamine Pyrimethamine, another benzylpyrimidine, selectively inhibits dihydrofolicacid reductase of protozoa compared with that of mammalian cells

Quonolones and Fluoroquinolones

Quinolones(Nalidixic acid)andFluoroquinolones(CiprofloxacinGatifloxacinGemifloxacinLevofloxacinLomefloxacinMoxifloxacinNorfloxacinOfloxacin)

Block bacterial DNA synthesis by inhibiting bacterial topoisomerase II(DNA gyrase) and topoisomerase IV. Inhibition of DNA gyrase preventsthe relaxation of positively supercoiled DNA that is required for normaltranscription and replication. Inhibition of topoisomerase IV interfereswith separation of replicated chromosomal DNA into the respectivedaughter cells during cell division.


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ANTIMYCOBACTERIAL DRUGSIsoniazid Isoniazid inhibits synthesis of mycolic acids, which are essential

components of mycobacterial cell walls. Isoniazid is a prodrug that isactivated by KatG, the mycobacterial catalase-peroxidase. The activatedform of isoniazid forms a covalent complex with an acyl carrier protein

(AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, whichblocks 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 fromany one of several possible point mutations in rpoB, the gene for thesubunit of RNA polymerase. These mutations result in reduced bindingof rifampin to RNA polymerase. Human RNA polymerase does not bindrifampin and is not inhibited by it. Rifampin is bactericidal formycobacteria.

Ethambutol Ethambutol inhibits mycobacterial arabinosyl transferases, which areencoded by the embCAB operon. Arabinosyl transferases are involved inthe polymerization reaction of arabinoglycan, an essential component of

the mycobacterial cell wall. Resistance to ethambutol is due to mutationsresulting in overexpression of emb gene products or within the embB structural gene.

Pyrazinamide Pyrazinamide is converted to pyrazinoic acid the active form of thedrug by mycobacterial pyrazinamidase, which is encoded by pncA. Thedrug target and mechanism of action are unknown. Resistance may bedue to impaired uptake of pyrazinamide or mutations in pncA that impairconversion of pyrazinamide to its active form.

Streptomycin See in Aminoglycoside section.

Second line drugsEthionamide 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. Paraaminosalicylicacid(PAS)

folate synthesis antagonist that is active almost exclusively against Mtuberculosis

Kanamycin& Amikacin

Discussed above.

Ciprofloxacin,Levofloxacin,Gatifloxacin, AndMoxifloxacin

Discussed above.

Linezolid Discussed above.Rifabutin Similar to Rifampicin.Rifapentine Similar to Rifampicin.

Anti-leprosy drugsDapsone(diaminodiphenylsulfone),Rifampicin

Discussed above

Clofazimine Clofazimine is a phenazine dye. Its mechanism of action is unknownbut may involve DNA binding.


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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 offungi, whereas the predominant sterol of bacteria and human cells is

cholesterol. Amphotericin B binds to ergosterol and alters thepermeability of the cell by forming amphotericin B-associated pores inthe cell membrane. As suggested by its chemistry, amphotericin Bcombines avidly with lipids (ergosterol) along the double bond-rich sideof its structure and associates with water molecules along the hydroxyl-rich side. This amphipathic characteristic facilitates pore formation bymultiple amphotericin molecules, with the lipophilic portions around theoutside of the pore and the hydrophilic regions lining the inside. The poreallows the leakage of intracellular ions and macromolecules, eventuallyleading to cell death. Some binding to human membrane sterols doesoccur, probably accounting for the drug's prominent toxicity

Flucytosine Flucytosine is taken up by fungal cells via the enzyme cytosinepermease. It is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridinetriphosphate (FUTP), which inhibit DNA and RNA synthesis,respectively. Human cells are unable to convert the parent drug to itsactive metabolites.

Azoles Azoles are synthetic compounds that can be classified as either imidazoles or triazoles. Theimidazoles consist of ketoconazole, miconazole, and clotrimazole . The triazoles includeitraconazole, fluconazole, and voriconazole.

Azoles The antifungal activity of azole drugs results from the reduction ofergosterol synthesis by inhibition of fungal cytochrome P450 enzymes.The specificity of azole drugs results from their greater affinity for fungalthan for human cytochrome P450 enzymes.

EchinocandinsCaspofungin,micafungin, andanidulafungin

Echinocandins act at the level of the fungal cell wall by inhibiting thesynthesis of (1 3) glucan. This results in disruption of the fungal cellwall and cell death.

Griseofulvin Griseofulvin's mechanism of action at the cellular level is unclear, but itis deposited in newly forming skin where it binds to keratin, protectingthe skin from new infection

Terbinafine Like griseofulvin, terbinafine is a keratophilic medication, but unlikegriseofulvin, it is fungicidal. Like the azole drugs, it interferes withergosterol biosynthesis, but rather than interacting with the P450system, terbinafine inhibits the fungal enzyme squalene epoxidase.This leads to the accumulation of the sterol squalene, which is toxic tothe organism.

Nystatin Nystatin is a polyene macrolide much like amphotericin B.


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Antiviral drugs

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

Acyclovir Acyclovir requires three phosphorylation steps for activation. It isconverted first to the monophosphate derivative by the virus-specifiedthymidine kinase and then to the di- and triphosphate compounds by hostcell enzymes . Because it requires the viral kinase for initialphosphorylation, acyclovir is selectively activated, and the activemetabolite accumulates, only in infected cells. Acyclovir triphosphateinhibits viral DNA synthesis by two mechanisms: competition withdeoxyGTP for the viral DNA polymerase, resulting in binding to the DNAtemplate as an irreversible complex; and chain termination followingincorporation into the viral DNA.

Valacyclovir Valacyclovir is the L-valyl ester of acyclovir. It is rapidly converted toacyclovir after oral administration via intestinal and hepatic first-passmetabolism

Famciclovir Famciclovir is the diacetyl ester prodrug of 6-deoxypenciclovir, After oraladministration, famciclovir is rapidly converted by first-pass metabolism topenciclovir. As with acyclovir, activation by phosphorylation is catalyzedby the virus-specified thymidine kinase in infected cells, followed bycompetitive inhibition of the viral DNA polymerase to block DNA

synthesis. Unlike acyclovir, however, penciclovir does not cause chaintermination. Penciclovir triphosphate has lower affinity for the viral DNA


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polymerase than acyclovir triphosphate, but it achieves higherintracellular concentrations and has a more prolonged intracellular effectin experimental systems.

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

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

Trifluridine Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside thatinhibits viral DNA synthesis. It is phosphorylated intracellularly to its activeform by host cell enzymes, and then competes with thymidinetriphosphate for incorporation by the viral DNA polymerase. Incorporationof trifluridine triphosphate into both viral and host DNA prevents itssystemic use.

Agents To Treat CytoMegaloVirus (CMV) Infections Ganciclovir Ganciclovir is an acyclic guanosine analog that requires activation by

triphosphorylation before inhibiting the viral DNA polymerase. Initialphosphorylation is catalyzed by the virus-specified protein kinasephosphotransferase UL97 in CMV-infected cells. The activated compoundcompetitively inhibits viral DNA polymerase and causes termination of viralDNA elongation

Valganciclovir Valganciclovir is an L-valyl ester prodrug of ganciclovir that exists as amixture of two diastereomers. After oral administration, both diastereomersare rapidly hydrolyzed to ganciclovir by intestinal and hepatic esterases.

Foscarnet(phosphonofor mic acid)

Foscarnet is an inorganic pyrophosphate compound that inhibits viral DNApolymerase, RNA polymerase, and HIV reverse transcriptase directlywithout requiring activation by phosphorylation.

Cidofovir In contrast to ganciclovir, phosphorylation of cidofovir to the activediphosphate is independent of viral enzymes. After phosphorylation,cidofovir acts both as a potent inhibitor of and as an alternative substratefor viral DNA polymerase, competitively inhibiting DNA synthesis andbecoming incorporated into the viral DNA chain.


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Antiretroviral drugs

Nucleoside & Nucleotide Reverse Transcriptase Inhibitors

The NRTIs act by competitive inhibition of HIV-1 reverse transcriptase and can alsobe incorporated into the growing viral DNA chain to cause termination. Each requiresintracytoplasmic 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 ofRNA- 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 withnucleoside triphosphates nor require phosphorylation to be active.


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Protease Inhibitors

During the later stages of the HIV growth cycle, the Gag and Gag-Pol gene productsare translated into polyproteins, and these become immature budding particles. Protease isresponsible for cleaving these precursor molecules to produce the final structural proteins of

the mature virion core. By preventing cleavage of the Gag-Pol polyprotein, proteaseinhibitors (PIs) result in the production of immature, noninfectious viral particles

Fusion InhibitorsEnfuvirtide (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, asynthetic 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 cellularmembranes.

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 intracellularsignals following binding to specific cell membrane receptors, resulting ininhibition of viral penetration, translation, transcription, proteinprocessing, maturation, and release, as well as increased expression ofmajor histocompatibility complex antigens, enhanced phagocytic activityof macrophages, and augmentation of the proliferation and survival ofcytotoxic T cells.

Adefovir dipivoxil Adefovir dipivoxil is the diester prodrug of adefovir, an acyclicphosphonated adenine nucleotide analog. It is phosphorylated by cellularkinases to the active diphosphate metabolite and then competitivelyinhibits HBV DNA polymerase to result in chain termination afterincorporation into the viral DNA.


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Entecavir Entecavir is an orally administered guanosine nucleoside analog (Figure49 2) that competitively inhibits all three functions of HBV DNApolymerase, including base priming, reverse transcription of the negativestrand, and synthesis of the positive strand of HBV DNA.

Ribavirin Ribavirin is a guanosine analog that is phosphorylated intracellularly by

host cell enzymes. Although its mechanism of action has not been fullyelucidated, it appears to interfere with the synthesis of guanosinetriphosphate, to inhibit capping of viral messenger RNA, and to inhibit theviral RNA-dependent polymerase of certain viruses.

ANTI-INFLUENZA AGENTS

Amantadine &Rimantadine

Amantadine (1-aminoadamantane hydrochloride) and its -methylderivative, rimantadine, are cyclic amines of the adamantine family thatblock the M2 proton ion channel of the virus particle and inhibit uncoatingof the viral RNA within infected host cells, thus preventing its replication.

They are active against influenza A only. Zanamivir &Oseltamivir

The neuraminidase inhibitors zanamivir and oseltamivir, analogs of sialicacid, interfere with release of progeny influenza virus from infected to newhost cells, thus halting the spread of infection within the respiratory tract.Unlike amantadine and rimantadine, zanamivir and oseltamivir haveactivity against both influenza A and influenza B viruses.

Palivizumab Palivizumab is a humanized monoclonal antibody directed against anepitope in the A antigen site on the F surface protein of RSV.

Imiquimod Imiquimod is an immune response modifier. The mechanism of actionagainst the human papillomavirus (HPV)-induced lesions is unknown.

METRONIDAZOLE, MUPIROCIN, POLYMYXINS

MetronidazoleTinidazole

The nitro group of metronidazole is chemically reduced in anaerobicbacteria and sensitive protozoans. Reactive reduction products appearto be responsible for antimicrobial activity.

Mupirocin Mupirocin (pseudomonic acid) inhibits staphylococcal isoleucyl tRNAsynthetase.

Polymyxin B &PolymyxinE(Colistin)

Polymyxins act like cationic detergents. They attach to and disruptbacterial cell membranes. They also bind and inactivate endotoxin.

URINARY ANTISEPTICS

Nitrofurantoin Methenamine Below pH 5.5, methenamine releases formaldehyde, which is

antibacterial.


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ANTIMALARIALSChloroquine

Amodiaquine Chloroquine probably acts by concentrating in parasite food vacuoles,preventing the polymerization of the hemoglobin breakdown product,heme, into hemozoin, and thus eliciting parasite toxicity due to thebuildup of free heme.

Quinine, quinidineMefloquinePrimaquineHalofantrineLumefantrine

Unknown

Atovaquone The mechanism of action of atovaquone is uncertain. In plasmodia itappears to disrupt mitochondrial electron transport.

Pyrimethamineand proguanil

selectively inhibit plasmodial dihydrofolate reductase

Sulfonamides andsulfones

inhibit another enzyme in the folate pathway, dihydropteroate synthase

Artemisinin The antimalarial activity of artemisinins may result from the productionof free radicals that follows the iron-catalyzed cleavage of theartemisinin endoperoxide bridge in the parasite food vacuole or frominhibition of a parasite calcium ATPase.

ANTI-HELMINTHICS AlbendazoleMebendazole

Benzimidazoles are thought to act against nematodes by inhibitingmicrotubule synthesis.

DEC Diethylcarbamazine immobilizes microfilariae and alters their surfacestructure, displacing them from tissues and making them moresusceptible to destruction by host defense mechanisms. The mode of

action against adult worms is unknown. Ivermectin Ivermectin appears to paralyze nematodes and arthropods by

intensifying -aminobutyric acid (GABA)-mediated transmission ofsignals in peripheral nerves.

Metrifonate(Trichlorfon)

Metrifonate, an organophosphate compound. The mode of action isthought to be related to cholinesterase inhibition. This inhibitiontemporarily paralyzes the adult worms, resulting in their shift from thebladder venous plexus to small arterioles of the lungs, where they aretrapped, encased by the immune system, and die.

Niclosamide Adult worms (but not ova) are rapidly killed, presumably due toinhibition of oxidative phosphorylation or stimulation of ATPase activity.

Piperazine Piperazine causes paralysis of ascaris by blocking acetylcholine at themyoneural junction; unable to maintain their position in the host, liveworms are expelled by normal peristalsis.

Praziquantel Praziquantel appears to increase the permeability of trematode andcestode cell membranes to calcium, resulting in paralysis,dislodgement, and death.

Pyrantel neuromuscular blocking agent that causes release of acetylcholine andinhibition of cholinesterase; this results in paralysis, which is followed byexpulsion of worms.

MOA Antibiotics

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