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Antimicrobial Drugs How were antimicrobial drugs first discovered? • Alexander Fleming – – – – 1928 S. aureus, Penicillium notatum Mass production: 1940s • Antibiosis – Lead to antibiotic – Different from chemotherapy! Where do antibiotics come from? • From other bacteria found in – Soil • Bacteria – Streptomyces: more than half! – Bacillus • Molds – Penicillium – Cephalosporium What is an antibiotic’s spectrum? • Number/types of organisms it affects • Narrow spectrum of antibiotic activity – Penicillin G: mostly only gram + • Broad spectrum antibiotic activity – Tetracycline – Pros vs cons – Lead to superinfections How do antimicrobial drugs work? • Depends on the drug – Bactericidal or bacteristatic • Modes of action include – Cell wall destruction – Inhibiting transcription or translation – Plasma membrane damage – Inhibiting DNA synthesis – Inhibiting synthesis of metabolites How can an antibiotic destroy the cell wall? • Penicillin and others • Prevent synthesis (crosslinking) • Cell then lyses due to weakened wall • Only affects actively growing cells • Does not affect humans Can you discuss some examples? • Penicillin – Penicillin G – Narrow spectrum, penicillinase susceptible • Penicillinase-resistant penicillins – Methicillin • MRSA – Replacing methicillin: oxacillin, nafcillin • Extended spectrum penicillins – Ampicillin, amoxicillin – Effective against both gram + and – • Cephalosporins – Penicillinase resistant, gram – effective • Vancomycin – Narrow spectrum – Last resort How can they inhibit protein synthesis? • Tetracyclines, chloramphenicol, streptomycin, etc. How do they injure the PM? • Polypeptide antibiotics (e.g. polymyxin B) • Change permeability of PM How do they inhibit DNA synthesis? • Limited usefulness… WHY? • Quinolones – Inhibits DNA gyrase – UTIs • Fluoroquinolones – Ciprofloxacin (Cipro) – Affects cartilage development – Can be used in adults How do they inhibit synthesis of important metabolites? • Competitive inhibition • Synthetic drug – Sulfaniamide inhibits paraaminobenzoic acid (PABA) – PABA is precursor for making folic acid – Sulfa prevents conversion – Humans don’t make folic acid, we eat it! Broad spectrum What are some antifungal drugs? • Many target fungal sterols – Ergosterol vs. (humans) cholesterol – Azoles • Athlete’s foot, yeast infection treatment • Others target chitin cell wall – Echinocandins • Many others which we won’t worry about… What about antiviral drugs? • Very few… WHY???? • Drugs can attack – – – – – Attachment Penetration Uncoating DNA/RNA synthesis Virion assembly Can you tell me about a couple? • Nucleosides and nucleotide analogs – Acyclovir: genital herpes – Interferons What tests are used to identify antimicrobial activity? • Disk-diffusion – Can’t determine bactericidal vs. stasis • Gradient diffusion • Broth dilution – Can determine bactericidal vs. stasis Effects of Combinations of Drugs • 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 What’s next? Is there a downside to antimicrobial or antibiotic use? • Yes! • Natural selection • Antibiotics – Always take the full prescription – They don’t work on viruses! What types of resistance are there? • video • Destruction of the drug (e.g. penicillinase) • Prevention of drug penetration – Common with tetracycline • Alteration of drug target site • Rapid efflux • Heredity – Transformation, transduction, transposons Resistance to Antibiotics Future of Chemotherapeutic Agents • Antimicrobial peptides – Broad-spectrum antibiotics • Nisin (lactic acid bacteria) • Magainin (frogs) • Cecropin (moths) • Antisense agents – Complementary DNA that binds • a pathogen's virulence gene(s) • and prevents transcription – Fomivirsen to treat CMV retinitis • siRNA – Complementary RNA that binds mRNA to inhibit translation