Antimicrobial Drugs

Antimicrobial DrugsChemotherapyThe use of drugs to treat a diseaseAntimicrobial drugsInterfere with the growth of microbes within a hostAntibioticSubstance produced by a microbe that, in small amounts, inhibits another microbeSelective toxicityA drug that kills harmful microbes without damaging the host

Historical PerspectiveTreatment hopeless before 1935 Paul Ehrlich, early 20th centuryFather of chemotherapy Fleming -- 1929 Penicillin discovered -- gram positives Florey -- 1940 Penicillin -- first therapeutic use Waksman -- 1944 Streptomycin -- gram negatives 1947 -- Chloramphenicol -- broad spectrum 1947 - present -- many

1928 Fleming discovered penicillin, produced by Penicillium.1940 Howard Florey and Ernst Chain performed first clinical trials of penicillin.Figure 20.1

Properties of an ideal antibioticbroad spectrumstable--long shelf lifesoluble in body fluidsstable toxicityNonallergenicreasonable costselectively toxicnot likely to induce bacterial resistance

Major genera that produce clinically useful antibiotics Bacillus StreptomycesCephalosporiumPenicillium

Major targets of antimicrobial activity

Cell wall synthesispenicillins, cephalosporins (beta-lactamase producing bacteria resistant to both, require active cell wall synthesis in actively growing cultures), bacitracin Cell membrane functionamphotericin B (no growth requirement, changes membrane permeability by binding to sterols in fungal membranes, more side effects since membranes similar in all cells) Protein synthesisAminoglycides, tetracyclines, chloramphenicol

Major targets of antimicrobial activityDNA synthesisTranslation (mRNA--> protein): Transcription: rifampin (TB), actinomycin D Block movement of ribosome along mRNA: streptomycin, tetracycline Prevent peptide bond formation by binding to ribosome: chloramphenicol, erythromycin

Antimetabolites (structural analogs of natural substances important in metabolism): PASA, sulfa drugs, INH PASA very similar in structure to PABA, required by bacteria (but not human cells) for synthesis of folic acid When PASA is used in synthesis of folic acid, results in nonfuctional folic acid analog and bacterial cell dies

Spectrum of Activity

The Action of Antimicrobial Drugs

The Action of Antimicrobial Drugs

PenicillinNatural penicillinsSemisynthetic penicillinsPenicilinase-resistant penicillinsExtended-spectrum penicillinsPenicillins + -lactamase inhibitorsCarbapenemsMonobactam

Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis

Antibacterial Antibiotics Inhibitors of Cell Wall SynthesisCephalosporins2nd, 3rd, and 4th generations more effective against gram-negativesPolypeptide antibioticsBacitracinTopical applicationAgainst gram-positivesVancomycinGlycopeptideImportant "last line" against antibiotic resistant S. aureus

ChloramphenicolBroad spectrumBinds 50S subunit, inhibits peptide bond formationAminoglycosidesStreptomycin, neomycin, gentamycinBroad spectrumChanges shape of 30S subunitAntibacterial Antibiotics Inhibitors of Protein Synthesis

TetracyclinesBroad spectrumInterferes with tRNA attachmentMacrolidesGram-positivesBinds 50S, prevents translocationErythromycinGram-positivesBinds 50S, prevents translocationAntibacterial Antibiotics Inhibitors of Protein Synthesis

Disk-Diffusion TestFigure 20.17

DefinitionsMIC Minimal inhibitory concentrationMBC Minimal bactericidal concentration

Broth Dilution TestFigure 20.19

A variety of mutations can lead to antibiotic resistance.Mechanisms of antibiotic resistance1. Enzymatic destruction of drug2. Prevention of penetration of drug3. Alteration of drug's target site4. Rapid ejection of the drugResistance genes are often on plasmids or transposons that can be transferred between bacteria.Antibiotic Resistance

Misuse of antibiotics selects for resistance mutants. Misuse includes:Using outdated, weakened antibioticsUsing antibiotics for the common cold and other inappropriate conditionsUse of antibiotics in animal feedFailure to complete the prescribed regimenUsing someone else's leftover prescriptionAntibiotic Resistance

Figure 20.20

Synergism occurs when the effect of two drugs together is greater than the effect of either alone.Antagonism occurs when the effect of two drugs together is less than the effect of either alone.Effects of Combinations of Drugs

Effects of Combinations of DrugsFigure 20.22

Antimicrobial peptidesBroad spectrum antibiotics from plants and animalsSqualamine (sharks)Protegrin (pigs)Magainin (frogs)Antisense agentsComplementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcriptionThe Future of Chemotherapeutic Agents

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