DrugResistance Flashcards
Intrinsic resistance
Due to natural properties of bacteria / mech of drug
Acquired resistance
Develops by genetic mutation or mobile genetic elements
Mobile genetic elements
Plasmids, transposons, bacteriophages
Broad categories of antibiotic resistance
(1) Inactivate/modify drug; (2) alter target; (3) reduce drug-target interaction
Antibiotic susceptibilities
R (resistant) ? don’t use the drug; S (susceptible) ? the drug might work
Porins
Hydrophilic channels in gram-neg outer membrane; mutation may impact drug uptake
Efflux pumps
Pumps in cell membrane of both gram-pos and -neg; may pump out multiple classes of drugs
Peptidoglycan
GlcNAc-MurNAc with 5 a.a. attached on MurNAc; assemble in cytoplasm, transported to membrane, surface
Transpeptidation
Amino acid cross-linking (in peptidoglycans), usually cleaves last D-ala (from D-ala-D-ala)
Transglycosylation
Joining of sugar molecules (in peptidoglycans)
Bacterial gram-staining class assoc with resistance
Gram-neg
Beta-lactam mech
Irreversibly binds PBPs and blocks transpeptidase fxn ? prevent peptide x-linking ? weaken cell wall ? ib cell growth
Beta-lactam resistance
(1) beta-lactamase; (2) altered PBPs w/ low affinity; (3) porin AND drug efflux
Beta-lactamases
Chr and plasmid; gram-pos and neg (most significantly gram-neg)
?Narrow? beta-lactamases
S. aureus ?bla? plasmid; E. Coli TEM-1 plasmid; K. pneum. SHV-1 Chr (all vs PCN, amp)
?Extended-spectrum beta-lactamases? (ESBLs)
mutants of TEM-1/2, SHV-1 allow more beta-lactams to ?fit?; mostly plasmid; primarily in E. coli and K. pneum
ampC
Chr gene encodes beta-lactamase degradinging all penicillins, 1st-3rd gen cephalosporins; Enterobacter, Pseudomonas, Serratia
ampC expression
Inducible by PCNs, 1st gen cephalosporins; Constitutive mutation ? breaks down all beta-lactams except carbapenems
Carbapenemases
KPC and NDM-1; mostly in K. pneum. and E. coli
Altered PBPs
(i) S. aureus ?mecA? PBP2a (=MRSA); (ii) Strep. Pneum. Mosaic PBP; (iii) Enterococci faecium PBP5
Vancomycin mech
Binds terminal D-ala-D-ala, physically blocks PBPs ? disrupt cell wall synth ? cell death
Vancomycin resistance ? enterococci
(2) VRE ?van? genes modify terminal D-ala-D-ala (e.g., vanA to D-ala-D-lac)
Vancomycin resistance ? S. aureus
(3) VISA thick peptidoglycan cell walls w/ less x-linking ? free D-ala-D-ala soaks up vancomycin
Quinolone mech
trap DNA gyrase or topoisomerase IV, resulting in release of lethal dsDNA breaks
Quinolone mech ? gram-neg
DNA gyrase
Quinolone mech ? gram-pos
Topoisomerase IV
Quinolone drug spectrum
Cipro targets DNA gyrase, so gram-neg; Moxifloxacin targets topo IV, so gram-pos; Levofloxacin targets both
QRDR
Quinolone resistance determining region
Quinolone resistance
Step-wise process; (1) rare; (2) point mutations in QRDR of DNA gyrase / topo IV; (3) mostly drug efflux (vs fluoroquinolones)
Macrolide mech
Bind to 23S rRNA component of 50S, preventing peptide chain elongation
Macrolide resistance
(1) rare; (2) ?erm? gene dimethylase enzyme dimethylates 23S rRNA; (3) mostly Chr/plasmid drug efflux
erm expression
Inducible by macrolides; constitutive affects macrolides but also clindamycin (same 23S rRNA binding site)
D-test
if macrolide resistance is erm (and not efflux), get D shape (and therefore should avoid clindamycin as well)
