Mechanisms of antimicrobial action and resistance; Beyond the cell wall
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Transcript of Mechanisms of antimicrobial action and resistance; Beyond the cell wall
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 resistanceMechanisms of antimicrobial resistance
Drug-modifying enzymes(e.g., - lactamases)
Altered drug targets (e.g., PBPs ribosomes, DNA gyrase)
Altered uptake oraccumulation of drug(e.g., altered porins, efflux)
Drug-modifying enzymes
• Aminoglycosides (enzyme add inactivating group the drug)–acetyltransferases
–phosphoryltransferases
–nucleotidyltransferases
• Fluoroquinolones–Aminoglycoside acetyltransferase has been modified
to acetylate ciprofloxacinShown on the next slide . . .
Modification and inactivation of ciprofloxacin
Ciprofloxacin (active) Acetyl-ciprofloxacin (inactive)
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
• 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 . . .
E
23S rRNA
ribosome
mRNA
tRNAgrowing polypeptide
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
Erythromycin cannot bind; protein synthesis proceeds
E
Inhibition of protein synthesis
Initiation Factors
30S mRNA50S
70SInitiation Complex
30S &mRNA
fMet-tRNALinezolid
Elongation FactorsElongation
Cycle
Termination
Peptide Product
ClindamycinMacrolidesTetracyclinesAminoglycosides
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
DNA damage byfluoroquinolone
FQ
Normal DNA gyrase function
Fluoroquinolone
Fluoroquinolones use DNA gyrase as a target
in Gram-negative bacteria
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