Chapter 20: Antimicrobial Drugs

1 Chapter 20: Antimicrobial Drugs2. Antibacterial Drugs1. Overview of Antimicrobial Drugs3. Antiviral Drugs4. Drugs for Eukaryotic Pathogens1. Overview of Antimicrobial DrugsAntibioticsAn antibioticis technically a substance produced a microorganism to inhibit or killother microorganisms: , the mold Penicillium chrysogenumproducespenicillinwhich kills Gram+bacteriaIn practice, though, the term antibioticis used to refer to anysubstance, natural or synthetic, that inhibits or kills microorganisms: when used therapeutically, antibiotics are Antimicrobial Drugs !Antibiotics should not harm the HostFor an antibioticto be an effective drug , it must cause significantly greater harm to the pathogen than to the host being treated: this requires the targeting of features of thepathogen that differ from the host s cells bacteria have several such targets such as thecell wall & ribosomes viruses and eukaryotic pathogens are muchmore challenging to treat since they have lessfeatures that can be safelytargetedEfficacy vs Toxicity the higher the chemotherapeutic index,the safer the of Antimicrobial DrugsThe range of pathogens targeted by a specificantibiotic is referred to as its spectrum, which can be broad or narrow.

2 Broad-spectrum antibiotics usually refers to Drugs effective against more that one general category of pathogens , Gram-& Gram+bacteria Narrow-spectrum antibiotics usually refers to Drugs effective against only one general category of pathogens , Gram+bacteria, or mycobacteriaExamples of Spectrum of Activity vancomycin is narrow spectrum tetracyclines are broad spectrumAntimicrobial drug ResistanceThe introduction of an antibiotic into the microbial environment is a selective factor that over time can select for resistant main ways to minimize this problem are:1) administer the antibiotic at the prescribeddose for the prescribed duration2) use antibiotics in combination premature stoppage allows the more resistantpathogens to survive much lower odds of resistance to multiple antibioticsHow is Resistance Obtained?

3 Resistance to an antibiotic is generally obtainedby the acquisition of antibiotic resistance , transformation, conjugation, transduction,or a fortuitous mutationResistance genes can be of several types: enzymesthat degrade the antibiotic pumpswhich rapidly expel the antibiotic barrierswhich resist penetration of antibiotic molecular changeswhich prevent binding ofthe antibiotic to the target site2. Antibacterial DrugsAntibacterial TargetsA variety of unique bacterial features can be targeted by antibiotics w/o harming host cells:1) bacterial cell wall peptidoglycan and outer membrane2) protein synthesis prokaryotic ribosomes differ from those of eukaryotes3) plasma membrane there are unique features to bacterial membranes4) nucleic acid synthesis unique features of prokaryotic DNA, RNA polymerases5) metabolic inhibitorsAntibacterial TargetsDrugs that Target the Cell WallInhibitors of peptidoglycan synthesis.

4 Penicillin & its derivatives over 50 related compounds some are natural, some are semisynthetic all penicillin-based compoundshave this same core structure prevent cross-linking of carbohydrate & peptidecomponents of peptidoglycan**more effective against Gram+bacteria (no outer membrane)**Some Penicillin DerivativesNatural produced byfungi narrow spectrum subject todegradationSemisynthetic side chain onlyis synthetic broaderspectrum resistant todegradationside chain ( R )Effects of Penicillin penetrates cells (mostly Gram+)and interferes with peptidoglycan synthesisbeforeafter without an intact peptidoglycan layer, bacterialcells are prone to lysis by osmosisMicrobial Defenses to Penicillin some bacteria can avoid the effects of penicillin by the production of penicillinases( , -lactamase), enzymes that break the -lactam ring semisynthetic derivatives such as Oxacillin areresistant to penicillinasesOther Peptidoglycan InhibitorsCephalosporin & its derivatives (over 70!)

5 Inhibits peptidoglycan synthesis much like penicillin resistant to penicillinases vulnerable to cleavage bya similar yet distinct classof enzymesVancomycin &Bacitracin polypeptides that inhibitpeptidoglycan synthesisin a different mannerDrugs that Target Protein SynthesisBacterial ribosomesare slightly smallerthan eukaryoticribosomes and haveenough structuraldifferences to makethem good targets for antibioticsTetracyclines block binding of tRNAs to ribosome Chloramphenicol blocks peptide bond formationAminoglycosides disrupt reading of mRNAI nhibitors of Nucleic Acid SynthesisRifamycins , rifampicin inhibit bacterial transcription (mRNA synthesis)Quinolones , ciprofloxacin broad spectrum antibiotic, more effective againstGram+bacteria penetrates host cells well, effective againstintracellular bacteria such as Mycobacteria inhibit the bacterial DNA gyrase - DNA replicationDrugs that target Plasma MembranePolymyxin B disrupts plasma membrane, outer membrane especially effective against Gram-bacteria usually in topical ointments ( over the counter )though can be given internallypolymyxin BMetabolic InhibitorsSome Drugs selectively inhibit metabolic processes in bacteria.

6 Sulfonamides ( sulfa Drugs ) inhibit folic acid synthesis from PABA (para-aminobenzoic acid) have a bacteriostatic effect synthetic compounds that have a broad spectrumof Antimicrobial activity different from folic acid synthesis in animalsAntimycobacterial DrugsMycobacteria are difficult targets due to theirunique acid-fast outer membrane containing mycolic acids, and being intracellular most effective antibiotics for mycobacterialinfections are:Rifamycins penetrate outer membrane, inhibit transcriptionIsoniazid directly inhibits mycolic acid synthesis3. Antiviral DrugsLimits of Antiviral DrugsViruses are especially difficult to target withdrugs for several reasons:1) viruses use host cell metabolic processes it s difficult to target viral processes w/o harming host2) viruses are intracellular parasites the drug must effectively enter host cells3) viruses can be latent there s very little a drug can do to combat a provirusNevertheless, there are a several antiviral Drugs in ) viruses mutate very rapidly thus their molecular targets can change rapidlyTargets of Antiviral DrugsAntiviral Drugs generally target the following.

7 Virus-specific enzymes , reverse transcriptase, integrase (inserts viral DNAinto host DNA), proteases (process viral proteins)Viral DNA replication, transcription Drugs inhibiting these processes may kill host cell also Fusionof enveloped viruses most enveloped viruses gain entry via fusion with thehost membrane which can also be blocked Nucleoside, Nucleotide AnalogsMany antiviral Drugs are analogs of nucleosides(sugar + base)or nucleotides (sugar + base + phosphate): incorporated into DNA or RNA acyclovir is a common antiviral drug that is ananalogue of thenucleosideguanosine function as chain terminators , preventing elongationAcyclovir: Mechanism of ActionThymidine kinase (TK) phosphorylates nucleosides to produce nucleotides for use in DNA viral TK will phosphorylate acyclovir which isincorporated into DNA by viral DNA polymerase blocksfurther elongationof DNA used with HerpesvirusesEnzyme InhibitorsSome antiviral Drugs bind directly to viral enzymes and inhibit their activity.

8 Protease inhibitors for many viral proteins to assemble into new viral particles, they must be cleaved by specific viral proteases protease inhibitors therefore can prevent viral maturationReverse transcriptase inhibitors unlike chain terminators like the nucleotide analogs,some Drugs directly inhibit reverse transcriptase activity prevents conversion of RNA to DNA, only effective against retroviruses such as HIVP roblems with Antiviral DrugsToxicity although antiviral preferentially inhibit viral factors, they can also inhibit host cell enzymes , nucleotide analogs are ~100 times more likely tobe used by viral polymerase than host polymerase, but this can still adversely affect host cellsSelection for resistant viruses due to viral evolution via mutation the use of antiviral Drugs in combination can minimizethis problem, though viruses tend to mutate rapidly4.

9 Drugs for EukaryoticPathogensChallenges of Eukaryotic PathogensUnlike bacteria, eukaryotic pathogens have lessfeatures that differ from host cells and thus less targets to work with: , ribosomes and other metabolic processes are basically the same as oursFor this reason there are fewer Drugs to turn toin order to treat eukaryotic infections, howeverthere are some unique features with which to target many eukaryotic of Antifungal DrugsFungal cells differ from animal cells like oursin the following ways thus providing targets for drug treatment: cell walls made of chitin fungal membranes have ergosterolas opposed to cholesterol targeted by the echinocandinclass of Drugs polyenes: a class of drugsthat are somewhat toxicamphotericin B (a polyene) azoles: a class of drugsused topically in manyantifungal creamsDrugs that Target Protists & HelminthsQuinine obtained from the cinchona tree in Peru used for centuries to treat malaria (Plasmodium vivax)Metronidazole (Flagyl) used for Trichomonas vaginalis, Giardia intestinalis inhibits anaerobic metabolismIvermectin produced by Streptomyces avermectinius paralyzes and kills many nematodesNiclosamide inhibits ATP production in tapewormsKey Terms for Chapter 20 penicillinase chain terminators nucleoside & nucleotide analogs ergosterol natural vs semisynthetic antibioticsRelevant Chapter Questions rvw: 1-10 MC: 1, 4-6, 9-12 broad vs narrow spectrum of activity all the various classes of Antimicrobial Drugs