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Mechanisms of antimicrobial action and resistance; Beyond the cell wall. Cary Engleberg, M.D. Division of Infectious Diseases, University of Michigan Medical School. Altered drug targets (e.g., PBPs ribosomes, DNA gyrase). Altered uptake or

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mechanisms of antimicrobial action and resistance beyond the cell wall

Mechanisms of antimicrobial action and resistance; Beyond the cell wall

Cary Engleberg, M.D.

Division of Infectious Diseases,

University of Michigan Medical School

mechanisms of antimicrobial resistance

Altered

drug

targets

(e.g., PBPs

ribosomes,

DNA gyrase)

Altered

uptake or

accumulation of

drug

(e.g., altered porins,

efflux)

Drug-modifying

enzymes

(e.g., - lactamases)

Mechanisms of antimicrobial resistance
drug modifying enzymes
Drug-modifying enzymes
  • Aminoglycosides (enzyme add inactivating group the drug)
    • acetyltransferases
    • phosphoryltransferases
    • nucleotidyltransferases
  • Fluoroquinolones
    • Aminoglycoside acetyltransferase has been modified to acetylate ciprofloxacin

Shown on the next slide . . .

modification and inactivation of ciprofloxacin
Modification and inactivation of ciprofloxacin

Acetyl-ciprofloxacin (inactive)

Ciprofloxacin (active)

altered drug targets
Altered drug targets
  • Ribosomes
    • macrolides and clindamycin
    • streptomycin
    • linezolid
  • DNA modifying enzymes
    • Fluoroquinolones
      • DNA gyrase (most important in Gram-negatives)
      • Topoisomerase II (most important in Gram-positives)
two mechanisms of macrolide resistance
Two mechanisms of macrolide resistance
  • Enhanced efflux of the antibiotic from the cell by an active membrane pump
  • Acquisition of an enzyme that methylates the 23S rRNA and blocks drug binding
    • depicted in the next slide . . .
slide7

mRNA

tRNA

growing polypeptide

23S rRNA

E

E

ribosome

Erythromycin cannot bind; protein synthesis proceeds

Erythromycin binds to the 23S rRNA subunit and blocks protein synthesis

In resistant strains, methylation of 23S rRNA binding site by an acquired enzyme occurs

inhibition of protein synthesis

30S &

mRNA

Initiation Factors

Linezolid

fMet-tRNA

70S

InitiationComplex

mRNA

30S

50S

Elongation Factors

Elongation Cycle

ClindamycinMacrolidesTetracyclinesAminoglycosides

Termination

Peptide Product

Inhibition of protein synthesis
resistance to linezolid
Resistance to linezolid
  • Originally thought to be unlikely given chemical origin and mode of action of the drug
  • 2 of 169 patients treated on a compassionate use protocol developed resistant strains
    • rRNA mutation (G2576U)
    • Both involved prolonged indwelling lines
  • Induction of resistance in the laboratory by prolonged passage:
    • in staphylococci, frequency is 10-9 - 10-11
    • among enterococci,E. faecalis is more likely to develop resistance (G2576U) than E. faecium
slide10

FQ

Fluoroquinolone

Fluoroquinolones use

DNA gyrase as a target

in Gram-negative bacteria

DNA damage by

fluoroquinolone

Normal DNA gyrase function

resistance by reducing the cytoplasmic concentration of antibiotics
Resistance by reducing the cytoplasmic concentration of antibiotics
  • Efflux pump systems exist in the cell membrane and transport small molecules out of the cytoplasm
  • The systems can be acquired genetically or undergo mutation to more efficiently eliminate a particular antibiotic
  • Commonly affected antibiotics
    • Tetracyclines (except tigecycline)
    • Macrolides (except telithromycin)
    • Fluoroquinolones