Antimicrobial chemotherapy

antimicrobial

any substance interferes with growth

antibiotics

substance produced by microbes; inhibits growth or kills other microbes

ideal antimicrobial drug

1. magic bullet

2. easy to dispense

3. can reach infectious agent

4. nontoxic to host

5. active long enough to cause

6. safely broken down/exreted

kirby-bauer

• disk diffusion test

• evaluates efficacy of chemical agent

• filter paper disks are soaked in a chemical and placed on a culture

• look for zone of inhibition around disk

E-test

• alternative diffusion test

• produce ZOI with strip

• strip has drug gradient

• determine MIC

tube dilution test

• sensitive, quantitative

• serial dilution of antimicrobial in tubes with broth

• inoculated with pure, incubated, examined for turbidity

• determine MIC and MBC

antimicrobial failure from…

1. drug can’t diffuse to infected body component

2. resistant microbes not detected in sample tested on

3. not microbicidal concentration for an immunocompromised patient

4. mixed infection, some resistant to drug

5. patient noncompliance

therapeutic index

ratio of drug dose toxic to humans compared to minimum effective dose

• smaller ratio:greater potential for toxic reaction

mechanism of antibiotic action

1. inhibition of cell wall synthesis

2. inhibition of protein synthesis

3. disruption of PM

4. inhibition of metabolic pathways

5. inhibition of nucleic acid

inhibition of cell wall synthesis

• target peptidoglycan layer

• prevent increasing amount of cell wall material

• no effect on existing cell wall

• only effective against bacterial cell growing reproducing

beta-lactam

penicillin; target crosslinkage of NAM subunit

glycopeptide

interfere with alanine-alanine bridges that link NAM (binds D-Ala-D-Ala); vancomycin 

bacitracin

blocks secretion og NAG and NAM

cyclic liopeptide (daptomycin)

forms micelles that penetrate cell membrane, oligomerizes, form membrane

polymyxin

induce chemical instability, eventual loss of physical integrity of membrane 

sulfonamides

target folic acid synthesis, structural analog of PABA disrupt cell metabolism for cell death

trimethoprim

also interferes with nucleic acid synthesis

quinolones

specifically target prokaryotic DNA gyrase enzyme or topoisomerase

rifamycin

inhibit synthesis of bacterial RNA, target prokaryotic DNA dep. RNA-polymerase, inhibits transcription initiation

antimicrobial resistance development

• persister cells

• spontaneous mutations

• RNAi epigenetic gene silencing

mechanism of drug resistance

• modification/inactivation drug

• permeability/uptake of drug lowered

• inhibit penetration to the target site within the microbe

• alter target site

• efflux 

antibiotic misuse

• overuse

• stopping early (not finishing full coarse of antibiotics)

  • prescribing for viral infection

alternative agents

• target virulence factors

• sequester iron, which feed pathogens

• antimicrobial peptides produced by various organisms

• phage theory

• predatory bacteria

• RNAi, CRISPR