1 / 12

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. Altered drug targets (e.g., PBPs ribosomes, DNA gyrase). Altered uptake or

benedict-cooke
Download Presentation

Mechanisms of antimicrobial action and resistance; Beyond the cell wall

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Mechanisms of antimicrobial action and resistance; Beyond the cell wall Cary Engleberg, M.D. Division of Infectious Diseases, University of Michigan Medical School

  2. 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

  3. 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 . . .

  4. Modification and inactivation of ciprofloxacin Acetyl-ciprofloxacin (inactive) Ciprofloxacin (active)

  5. 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)

  6. 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 . . .

  7. 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

  8. 30S & mRNA Initiation Factors Linezolid fMet-tRNA 70S InitiationComplex mRNA 30S 50S Elongation Factors Elongation Cycle ClindamycinMacrolidesTetracyclinesAminoglycosides Termination Peptide Product Inhibition of protein synthesis

  9. 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

  10. FQ Fluoroquinolone Fluoroquinolones use DNA gyrase as a target in Gram-negative bacteria DNA damage by fluoroquinolone Normal DNA gyrase function

  11. Efflux pumps

  12. 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

More Related