Document Report Card

ID: ALA1255335

Journal: Antimicrob Agents Chemother

Title: The Lys234Arg substitution in the enzyme SHV-72 is a determinant for resistance to clavulanic acid inhibition.

Authors: Mendonça N, Manageiro V, Robin F, Salgado MJ, Ferreira E, Caniça M, Bonnet R.

Abstract: The new beta-lactamase SHV-72 was isolated from clinical Klebsiella pneumoniae INSRA1229, which exhibited the unusual association of resistance to the amoxicillin-clavulanic acid combination (MIC, 64 microg/ml) and susceptibility to cephalosporins, aztreonam, and imipenem. SHV-72 (pI 7.6) harbored the three amino acid substitutions Ile8Phe, Ala146Val, and Lys234Arg. SHV-72 had high catalytic efficiency against penicillins (k(cat)/K(m), 35 to 287 microM(-1) x s(-1)) and no activity against oxyimino beta-lactams. The concentration of clavulanic acid necessary to inhibit the enzyme activity by 50% was 10-fold higher for SHV-72 than for SHV-1. Molecular-dynamics simulation suggested that the Lys234Arg substitution in SHV-72 stabilized an atypical conformation of the Ser130 side chain, which moved the O gamma atom of Ser130 around 3.5 A away from the key O gamma atom of the reactive serine (Ser70). This movement may therefore decrease the susceptibility to clavulanic acid by preventing cross-linking between Ser130 and Ser70.

CiteXplore: 18316518

DOI: 10.1128/aac.01381-07