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Antimicrobial Drugs

Antimicrobial Drugs. Antimicrobial Drugs. Chemotherapy The use of drugs to treat a disease Antimicrobial drugs Interfere with the growth of microbes within a host Antibiotic Substance produced by a microbe that, in small amounts, inhibits another microbe Selective toxicity

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Antimicrobial Drugs

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  1. Antimicrobial Drugs

  2. Antimicrobial Drugs • Chemotherapy • The use of drugs to treat a disease • Antimicrobial drugs Interfere with the growth of microbes within a host • Antibiotic • Substance produced by a microbe that, in small amounts, inhibits another microbe • Selective toxicity • A drug that kills harmful microbes without damaging the host

  3. Historical Perspective • Treatment hopeless before 1935 • Paul Ehrlich, early 20th century • Father 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

  4. 1928 – Fleming discovered penicillin, produced by Penicillium. • 1940 – Howard Florey and Ernst Chain performed first clinical trials of penicillin. Figure 20.1

  5. Properties of an ideal antibiotic • broad spectrum • stable--long shelf life • soluble in body fluids • stable toxicity • Nonallergenic • reasonable cost • selectively toxic • not likely to induce bacterial resistance

  6. Major genera that produce clinically useful antibiotics • Bacillus • Streptomyces • Cephalosporium • Penicillium

  7. Major targets of antimicrobial activity • Cell wall synthesis • penicillins, cephalosporins (beta-lactamase producing bacteria resistant to both, require active cell wall synthesis in actively growing cultures), bacitracin • Cell membrane function • amphotericin B (no growth requirement, changes membrane permeability by binding to sterols in fungal membranes, more side effects since membranes similar in all cells) • Protein synthesis • Aminoglycides, tetracyclines, chloramphenicol

  8. Major targets of antimicrobial activity • DNA 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

  9. Spectrum of Activity

  10. The Action of Antimicrobial Drugs

  11. The Action of Antimicrobial Drugs

  12. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Natural penicillins • Semisynthetic penicillins • Penicilinase-resistant penicillins • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors • Carbapenems • Monobactam

  13. Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Cephalosporins • 2nd, 3rd, and 4th generations more effective against gram-negatives • Polypeptide antibiotics • Bacitracin • Topical application • Against gram-positives • Vancomycin • Glycopeptide • Important "last line" against antibiotic resistant S. aureus

  14. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Chloramphenicol • Broad spectrum • Binds 50S subunit, inhibits peptide bond formation • Aminoglycosides • Streptomycin, neomycin, gentamycin • Broad spectrum • Changes shape of 30S subunit

  15. Antibacterial Antibiotics Inhibitors of Protein Synthesis • Tetracyclines • Broad spectrum • Interferes with tRNA attachment • Macrolides • Gram-positives • Binds 50S, prevents translocation • Erythromycin • Gram-positives • Binds 50S, prevents translocation

  16. Disk-Diffusion Test Figure 20.17

  17. MIC Minimal inhibitory concentration MBC Minimal bactericidal concentration Definitions

  18. Broth Dilution Test Figure 20.19

  19. Antibiotic Resistance • A variety of mutations can lead to antibiotic resistance. • Mechanisms of antibiotic resistance 1. Enzymatic destruction of drug 2. Prevention of penetration of drug 3. Alteration of drug's target site 4. Rapid ejection of the drug • Resistance genes are often on plasmids or transposons that can be transferred between bacteria.

  20. Antibiotic Resistance • Misuse of antibiotics selects for resistance mutants. Misuse includes: • Using outdated, weakened antibiotics • Using antibiotics for the common cold and other inappropriate conditions • Use of antibiotics in animal feed • Failure to complete the prescribed regimen • Using someone else's leftover prescription

  21. Figure 20.20

  22. 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.

  23. Effects of Combinations of Drugs Figure 20.22

  24. The Future of Chemotherapeutic Agents • Antimicrobial peptides • Broad spectrum antibiotics from plants and animals • Squalamine (sharks) • Protegrin (pigs) • Magainin (frogs) • Antisense agents • Complementary DNA or peptide nucleic acids that binds to a pathogen's virulence gene(s) and prevents transcription

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