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
Penicillin discovered -- gram positives
Florey
Penicillin -- first therapeutic use
Waksman
Streptomycin -- gram negatives
Chloramphenicol -- broad spectrum
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
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

16. Disk-Diffusion Test
Figure 20.17

17. Definitions MIC Minimal inhibitory concentration
MBC Minimal bactericidal concentration

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