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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 • 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
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
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 antibiotic • broad spectrum • stable--long shelf life • soluble in body fluids • stable toxicity • Nonallergenic • reasonable cost • selectively toxic • not likely to induce bacterial resistance
Major genera that produce clinically useful antibiotics • Bacillus • Streptomyces • Cephalosporium • Penicillium
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
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
Antibacterial Antibiotics Inhibitors of Cell Wall Synthesis • Penicillin • Natural penicillins • Semisynthetic penicillins • Penicilinase-resistant penicillins • Extended-spectrum penicillins • Penicillins + -lactamase inhibitors • Carbapenems • Monobactam
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
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
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
Disk-Diffusion Test Figure 20.17
MIC Minimal inhibitory concentration MBC Minimal bactericidal concentration Definitions
Broth Dilution Test Figure 20.19
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.
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
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.
Effects of Combinations of Drugs Figure 20.22
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