MICR 201 Microbiology for Health Related Sciences

1. Lecture 19: Antimicrobial Chemotherapy Edith Porter, M.D. MICR 201 Microbiology for Health Related Sciences

2. Lecture outline • History of antimicrobial drug discovery • Antimicrobial drugs: definitions and keyproducers • Antibacterial drugs • Targets • Classes • Anti-tuberculosis drugs • Mechanisms of resistance • Antifungal drugs • Antiviral drugs • Drugs against protozoa and helminths • Drugs important for case studies

3. Milestones in antimicrobial therapy • Paul Ehrlich develops hypothesis of “magic bullet” while working on dyes and stains • Something that selectively finds and destroys a pathogen but does not harm surrounding tissue • 1928 Alexander Fleming observes and interprets correctly inhibition of S. aureus by contaminating Penicilliumculture • Golden age of antimicrobial drug discoveries ~ 1940 – 1960 • Since then few new developments for antibacterial drugs

4. Challenge of antimicrobial drugs • Must be absorbed • Must work in the host without damaging the host • Use targets that are specific to microorganism • Easier for antibacterial drugs • More difficult for drugs against eukaryotic pathogens • Very difficult against viruses

5. Antimicrobial drugs: definitions • Antibiotic • Substance produced by living microorganism that in small quantities inhibits other bacteria (and less often fungi) • Note: some antibiotics are anti-cancer drugs • Sometimes this term is used for all classes of antimcirobial agents • Chemotherapeutic • Synthetic antimicrobial drug • Newer generation of antibiotics are synthetic versions of naturally occurring antibiotics • Antibacterial, antimycobacterial, antifungal, antiviral, antiprotozoan, antiheminthic • Antimicrobics • Includes all types of drugs used to treat infectious diseases

6. The action of antimicrobials • -cidal: killing, reducing numbers of viable microbes • -static: preventing growth and proliferation Add antimicrobial CFU/ml Time [h]

7. Antibiotic producers • Typically soil organisms • Bacteria • > 50% Streptomyces • Bacillus • Fungi • Penicillium • Cephalosporium

8. Major modes of action of A\antimicrobial drugs

9. Cell wall Bacitracin Penicillin Cephalosporin Vancomycin Plasma membrane Polymyxin B Antimetabolite Sulfa drugs (inhibit purine and pyrimidine synthesis) Replication Quinolone Ciprofloxacin Transcription Rifampin Protein synthesis Chloramphenicol Macrolides Erythromycin Tetracyclin Aminoglycosides Gentamicin Streptomycin Streptogramin Oxazolidinones Against MRSA Mode of action of selected Antibacterial Antibiotics

10. Penicillin treated bacterium

11. Antimetabolites • Sulfa drugs among the first synthetic drugs • Cotrimoxazol • Still in use against urinary tract infections • Also for Pneumocystis infection in AIDS • Inhibits folic acid synthesis • Coenzyme for purine and pyrimidine synthesis • Affects nucleic acid and amino acid synthesis • Humans take up folic acid with food

12. Major unwanted side effects of antibacterial drugs • In general • Allergies • Gastrointestinal disturbances of normal flora (C. difficile pseudomembranousenterocolitis) • Penicillin, cephalosporines • Allergies • Aminoglycosides • Oto- and nephrotoxic • Tetracycline • Discoloration of teeth • Chloramphenicol • Bone marrow suppression

13. Antimycobacterialdrugs • Treatment of tuberculosis • Mycobacterium tuberculosis • Slow growth • Lipid rich cell wall (mycolic acids) • Long term combination therapy • Drugs reserved for use in tuberculosis • Isoniazid (INH) • Inhibits mycolic acid synthesis • Ethambutol • Inhibits mycolic acid incorporation into cell wall • Drugs used also elsewhere • Rifampin • Streptomycin Acid fact stain of lung tissue smear

14. Important antifungal drugs • Amphotericin B • Systemic infections • toxic • Azoles • Clotrimazole, miconazole (topic) • Fluconazole (systemic) • Echinocandins • Flucytosin • Griseofulvin • Skin, nails (topic) • Tolnaftate • Athlete’s foot (topic) Target Plasma membrane (ergosterols) Cell wall Protein synthesis Mitotic microtubuli ?

15. Injury of yeast plasma membrane by miconazole

16. Important antiparasiticdrugs • Antiprotozoan • Chloroquine: malaria • Metronidazol: giardiasis, amebiasis, trichomoniasis • also active against anaerobic bacteria • Antihelminthic • Niclosamide • Tapeworms • Praziquantel • Tapeworms, flukes • Mebendazol • Intestinal round worm

17. Act on Virus Inhibitor of neuraminidase Zanamivir, oseltamivir or tamiflu (influenza) Inhibitor of uncoating Amantadine (Influenza) Nucleoside and nucleotide analogs Acyclovir, ganciclovir (Herpes) Reverse transcriptase inhibitors Zidovudine, tenofovir, delavirdine (HIV) Integrase inhibitor Protease inhibitors Indinavir, ritonavir (HIV) Fusion inhibitor Stimulate Host Defense Interferons (Hepatitis) Important antiviral drugs

18. Spectrum of antimicrobial activity • Narrow spectrum: active against a few types of microorganisms • Broad spectrum: active against various types of microorganisms (including normal flora!)

19. Synergistic Activity • Synergism: effect of two drugs together is greater than the effect of either alone • Antagonism: effect of two drugs together is less than the effect of either alone

20. Development of antibiotic resistant mutants during antibiotic therapy

21. Misuse of antibiotics selects for resistant mutants • Outdated, expired antibiotics • Antibiotics for the common cold (virus infection) and other inappropriate conditions • Use of antibiotics in animal feed • Failure to complete the prescribed regimen • Using someone else's leftover prescription

22. Mechanisms of microbial resistance (1) • Enzymatic destruction of drug (ß-Lactamases) • Prevention of penetration of drug • Alteration of drug's target site • Rapid ejection of the drug (Efflux Pumps) • Resistance genes are often on plasmids or transposons that can be transferred between bacteria

23. Mechanisms of microbial resistance (2)

24. Novel antimicrobial drugs • Antimicrobial peptides • Broad spectrum antibiotics • Cell membrane targeted • Protegrins (from pigs) in clinical trial • Nisin • Bacterial compound known as food preservative • Antisense agents • Complementary DNA that binds to a pathogen's virulence gene(s) and prevents transcription • siRNA (short interfering RNA)

25. Important to remember • Antibiotic is made by a microorganism and inhibits other microorganisms; chemotherapeutica are synthetic • Cidal: kills; static: inhibits growth • Narrow spectrum antimicrobial affects a few strains, broad spectrum many strains • Synergism: more effect than the sum of the effects of each compound alone; antagonism: less effect than the sum of the effect of each component alone • Antibacterial/antimycobacterial/antifungal/antiviral/antiprotozoanand antihelminthic drugs differ • Special regime for tuberculosis • Resistance induced by improper use of antibiotics

26. Last not least