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 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

Spectrum of Activity

The Action of Antimicrobial Drugs

The Action of Antimicrobial Drugs

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 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

Disk-Diffusion Test Figure 20.17

Definitions MIC Minimal inhibitory concentration MBC Minimal bactericidal concentration

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

Figure 20.20

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