Lecture 19: Antimicrobial Chemotherapy
Edith Porter, M.D.
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History of antimicrobial drug discovery
Antimicrobial drugs: definitions and keyproducers
Antibacterial drugs
 Targets
 Classes
 Anti-tuberculosis drugs
 Mechanisms of resistance
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Antifungal drugs
Antiviral drugs
Drugs against protozoa and helminths
Drugs important for case studies
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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
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Must be absorbed
Must work in the host without damaging the host
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Use targets that are specific to microorganism
 Easier for antibacterial drugs
 More difficult for drugs against eukaryotic pathogens
 Very difficult against viruses
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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
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Chemotherapeutic
 Synthetic antimicrobial drug
 Newer generation of antibiotics are synthetic versions of naturally
occurring antibiotics
Antibacterial, antimycobacterial, antifungal, antiviral,
antiprotozoan, antiheminthic
 Antimicrobics
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 Includes all types of drugs used to treat infectious diseases
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-cidal: killing, reducing numbers of viable microbes
-static: preventing growth and proliferation
CFU/ml
Add
antimicrobial
Time [h]
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Typically soil organisms
Bacteria
 > 50% Streptomyces
 Bacillus
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Fungi
 Penicillium
 Cephalosporium
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Cell wall
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Bacitracin
Penicillin
Cephalosporin
Vancomycin
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Transcription
 Rifampin
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Protein synthesis
 Chloramphenicol
 Macrolides
▪ Erythromycin
 Plasma membrane
 Tetracyclin
 Polymyxin B
 Aminoglycosides
 Antimetabolite
▪ Gentamicin
 Sulfa drugs (inhibit purine and ▪ Streptomycin
pyrimidine synthesis)
 Streptogramin
 Replication
 Oxazolidinones
 Quinolone
▪ Against MRSA
▪ Ciprofloxacin
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Sulfa drugs among the first synthetic drugs
 Cotrimoxazol
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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
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Humans take up folic acid with food
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In general
 Allergies
 Gastrointestinal disturbances of normal flora (C. difficile 
pseudomembranous enterocolitis)
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Penicillin, cephalosporines
 Allergies
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Aminoglycosides
 Oto- and nephrotoxic
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Tetracycline
 Discoloration of teeth
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Chloramphenicol
 Bone marrow suppression
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Treatment of tuberculosis
Mycobacterium tuberculosis
 Slow growth
 Lipid rich cell wall (mycolic acids)
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Long term combination therapy
Drugs reserved for use in
tuberculosis
 Isoniazid (INH)
▪ Inhibits mycolic acid synthesis
 Ethambutol
▪ Inhibits mycolic acid incorporation into
cell wall
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Drugs used also elsewhere
 Rifampin
 Streptomycin
Acid fact stain of lung tissue smear
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Amphotericin B
 Systemic infections
 toxic
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Azoles
 Clotrimazole, miconazole (topic)
 Fluconazole (systemic)
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Echinocandins
Flucytosin
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Griseofulvin
 Skin, nails (topic)
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Tolnaftate
 Athlete’s foot (topic)
Target
Plasma membrane
(ergosterols)
Cell wall
Protein synthesis
Mitotic microtubuli
?
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Antiprotozoan
 Chloroquine: malaria
 Metronidazol: giardiasis, amebiasis, trichomoniasis
▪ also active against anaerobic bacteria
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Antihelminthic
 Niclosamide
▪ Tapeworms
 Praziquantel
▪ Tapeworms, flukes
 Mebendazol
▪ Intestinal round worm
Act on Virus
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Inhibitor of neuraminidase
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Inhibitor of uncoating
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Zidovudine, tenofovir, delavirdine
(HIV)
Integrase inhibitor
Protease inhibitors
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Acyclovir, ganciclovir (Herpes)
Reverse transcriptase inhibitors
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Amantadine (Influenza)
Nucleoside and nucleotide
analogs
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Zanamivir, oseltamivir or tamiflu
(influenza)
Indinavir, ritonavir (HIV)
Fusion inhibitor
Stimulate Host Defense
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Interferons (Hepatitis)
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Narrow spectrum: active against a few types of
microorganisms
Broad spectrum: active against various types of
microorganisms (including normal flora!)
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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
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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
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Nisin
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Broad spectrum antibiotics
Cell membrane targeted
Protegrins (from pigs) in clinical trial
Bacterial compound known as food preservative
Antisense agents
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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
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Target microorganism
Suggested antimicrobial
drug
Comments
MRSA (nosocomial)
Vancomycin
C. trachomatis
Doxycycline
Treat sex partner as well
S. typhimurium
None
Symptomatic primarily
(oral fluids)
M. tuberculosis
INH & Rifampin
(ethambutol ,
pyrazinamid)
Combination therapy, at
least 6 months – 12
months
HIV
Reverse transcriptase
inhibitor
Integrase inhibitor
Protease inhibitor
Combination therapy
Severe side effects
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