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MICR 201 Microbiology for Health Related Sciences

Lecture 19: Antimicrobial ChemotherapyEdith Porter, M.D.

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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

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 Penicillium culture

Golden age of antimicrobial drug discoveries ~ 1940 – 1960

Since then few new developments for antibacterial drugs

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

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

The action of antimicrobials

-cidal: killing, reducing numbers of viable microbes

-static: preventing growth and proliferation

Time [h]

CFU/

ml

Addantimicrobi

al

Antibiotic producers

Typically soil organisms Bacteria

> 50% Streptomyces Bacillus

Fungi Penicillium Cephalosporium

Major modes of action of A\antimicrobial drugs

Mode of action of selected Antibacterial Antibiotics

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

Penicillin treated bacterium

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

Major unwanted side effects of antibacterial drugs 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

Antimycobacterial drugs 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

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)

Plasma membrane

(ergosterols)

Mitotic microtubuli

Cell wall

Target

Protein synthesis

?

Injury of yeast plasma membrane by miconazole

Important antiparasitic drugs Antiprotozoan

Chloroquine: malaria Metronidazol: giardiasis, amebiasis,

trichomoniasis▪ also active against anaerobic bacteria

Antihelminthic Niclosamide▪ Tapeworms

Praziquantel▪ Tapeworms, flukes

Mebendazol▪ Intestinal round worm

Important antiviral drugs

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)

Spectrum of antimicrobial activity

Narrow spectrum: active against a few types of microorganisms

Broad spectrum: active against various types of microorganisms (including normal flora!)

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

Development of antibiotic resistant mutants during antibiotic therapy

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

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

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Mechanisms of microbial resistance (2)

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)

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/antiprotozoan and antihelminthic drugs differ

Special regime for tuberculosis Resistance induced by improper use of

antibiotics

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Last not least

Target microorganism

Suggested antimicrobial drug

Comments

MRSA (nosocomial) VancomycinC. trachomatis Doxycycline Treat sex partner as

wellS. typhimurium None Symptomatic

primarily (oral fluids)M. tuberculosis INH & Rifampin

(ethambutol , pyrazinamid)

Combination therapy, at least 6 months – 12 months

HIV Reverse transcriptase inhibitorIntegrase inhibitorProtease inhibitor

Combination therapySevere side effects