Lecture 19: Antimicrobial Chemotherapy Edith Porter, M.D. 1

2  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

 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 Penicillium culture  Golden age of antimicrobial drug discoveries ~ 1940 – 1960  Since then few new developments for antibacterial 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

 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

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

 Typically soil organisms  Bacteria  > 50% Streptomyces  Bacillus  Fungi  Penicillium  Cephalosporium

 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

 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

 In general  Allergies  Gastrointestinal disturbances of normal flora (C. difficile  pseudomembranous enterocolitis)  Penicillin, cephalosporines  Allergies  Aminoglycosides  Oto- and nephrotoxic  Tetracycline  Discoloration of teeth  Chloramphenicol  Bone marrow suppression

 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

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

 Antiprotozoan  Chloroquine: malaria  Metronidazol: giardiasis, amebiasis, trichomoniasis ▪ also active against anaerobic bacteria  Antihelminthic  Niclosamide ▪ Tapeworms  Praziquantel ▪ Tapeworms, flukes  Mebendazol ▪ Intestinal round worm

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)

 Narrow spectrum: active against a few types of microorganisms  Broad spectrum: active against various types of microorganisms (including normal flora!)

 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

 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

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

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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)

 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/anti protozoan and antihelminthic drugs differ  Special regime for tuberculosis  Resistance induced by improper use of antibiotics

Target microorganismSuggested antimicrobial drug Comments MRSA (nosocomial)Vancomycin C. trachomatisDoxycyclineTreat sex partner as well S. typhimuriumNoneSymptomatic primarily (oral fluids) M. tuberculosisINH & Rifampin (ethambutol, pyrazinamid) Combination therapy, at least 6 months – 12 months HIVReverse transcriptase inhibitor Integrase inhibitor Protease inhibitor Combination therapy Severe side effects 26