Microbial Growth Control III - Antibiotic Resistance

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  1. How can you help limit the development of resistant strains?
    • don't demand antibiotics - tend to be overprescribed
    • if you become a doctor, prescribe correct dosage and duration. consider use of two antibiotics with different modes of action in concert
    • follow directions and take dose at correct time intervals for full course
    • if you work in animal husbandry, limit antibiotics use to therapeutics treatment only and choose the antibiotic carefully
    • limit exposure in hospitals
  2. *antimicrobial resistance mechanisms
    • reduce antibiotic concentration in cell:
    • impermeable to antibiotic
    • *efflux pumps - allows multiple resistance
    • prevent uptake

    • inactivate antibiotic:
    • organisms may alter antibiotic to inactivate form

    lack target or modified target:

    develop a metabolic pathway that isn't targeted
  3. *How did antibiotic resistance plasmids originate?
    developed in microbes that produced antibiotics and then transfered to other microbes in the same niche
  4. mechanisms of resistance to tetracycline
    • efflux pump
    • cytoplasmic protein protects ribosome from tetracycline
    • protein that modifies tetracycline to inactive form, which then diffuses out of the cell
  5. tetracycline resistance genes
    • efflux and detoxification resistance mechanisms - on plasmid
    • target protection - plasmid and chromosome
  6. *resistance development in the lab vs. clinical isolates
    • lab - resistance due to chromosomal alterations
    • usually due to modification of antibiotic target
    • don't have extensive repertoire of microorganisms interacting and as a resource for transfer of R factors

    • clinical isolates - due to drug resistance genes on R plasmids
    • usually due to inactivation of the antibiotic or efflux
    • antibiotic treatment can actually increase R transfer via conjugation
  7. antibiotic discovery
    • 1. identify new targets using genomic information, nice if it is target humans don't have, could also be a protein that is only expressed in vivo
    • 2. Find (from natural isolate or from chemical library screens) or design compounds that inhibit the target in vitro and then show that the compound also inhibits bacterial growth
    • 3. Show that the target within the bacterial cell is the same as the in vitro target
    • 4. Optimize the MICs against susceptible species by altering the compound's structure- retest mechanism of action
    • 5. examine the compound's spectrum of activity and the rate at which antibiotic resistance develops
    • 6. determine the new antibiotic's toxicity to animals and humans and its pharmacological properties
  8. Platensimycin
    • new chemical class of antibiotic
    • target pathway: fatty acid biosynthesis differs in prokaryotes vs. eukaryotes
    • chemical lab screening to identify compounds that inhibit fatty acid biosynthesis
    • focused on the FabF protein - conserved among key pathogens and essential compound of fatty acid biosynthesis
    • engineered S. aureus to produce less FabF protein - increase ability to detect difference
    • MIC would be lower and better able to identify
  9. new antimicrobial drugs
    • new targets
    • approaches:
    • computerized drug design against specific targets
    • combinatorial chemistry
    • mechanism of action classification and target prediction (transcription and protein profiling)
  10. mechanism of action classification and target prediction by protein and mRNA expression profiling
    • antibiotic compound of unknown MOA
    • microarray hybridization/ 2D gel run
    • quality assessment of mRNA/ protein profiles
    • reference compendium-based classification and pathway/regulon mapping
    • MOA class and target prediction
  11. new approaches to known targets example
    • design antibiotic nanotubes to disrupt membrane
    • cycle peptides with alternating D- and L- amino acids
    • these cyclic peptides effectively poke holes in the membrane and disrupt normal electrical potential and ion gradients
    • can optimize for membrane composition of bacteria cs. humans
Card Set
Microbial Growth Control III - Antibiotic Resistance
general microbiology midterm 3
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