Carbapenems as inhibitors of OXA-13, a novel, integron-encoded β-lactamase in Pseudomonas aeruginosa

Abstract

A clinical Pseudomonas aeruginosa strain, PAe391, was found to be resistant to a number of antibiotics including ticarcllin, piperacillin, cefsulodin and amikacin, and a disk diffusion assay showed evidence of pronounced synergy between imipenem and various β;-lactam antibiotics. Cloning and nucleotide sequence analysis revealed the dicistronic arrangement of an aac(6’)-lb variant and a novel bla OXA-type gene between the intl and qacEδ1 genes typical of integrons. In PAe391, this integron was apparently chromosome-borne. The β;-lactamase, named OXA-13, displayed nine amino acid changes with respect to OXA-10: I in position 10 of OXA-10 to T (I10T), G20S, D55N, N73S, T107S, Y174F, E229G, S245N and E259A. OXA-13 (plapp = 8.0) showed poor catalytic activity against penicillins as well as cephalosporins, but was efficient in hydrolysing some penicillinase-resistant β;-lactams, such as cefotaxime and aztreonam. It was efficiently inhibited by imipenem (K iapp = 11 nM), and formed a stable complex. While the K iapp value of meropenem was similar (16 nM), the corresponding complex was less stable.