Structure and Dynamics of Burkholderia pseudomallei OXA-57, a Distinctive Low-Efficiency Class D β-Lactamase with Carbapenem-Hydrolyzing Activity

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Abstract The Gram-negative bacterium Burkholderia pseudomallei causes the severe disease melioidosis. β-Lactams, including carbapenems, are the primary treatment for B. pseudomallei infections, but are susceptible to chromosomal serine β-lactamases (SBLs), including the class D enzyme OXA-57. Here we show that recombinant OXA-57 is active toward penicillins and first-generation cephalosporins, slowly hydrolyzes carbapenems, including imipenem and meropenem, but is inactive toward oxyimino-cephalosporins (e.g., ceftazidime). Unlike many OXA enzymes, OXA-57 is sensitive to the mechanism-based SBL inhibitor clavulanic acid, but less so to the diazabicyclooctane avibactam and not to the cyclic boronate vaborbactam. Crystal structures of covalent OXA-57:avibactam and OXA-57:meropenem complexes reveal limited hydrogen-bonding interactions with bound ligands. In molecular dynamics simulations, the bound meropenem acyl-enzyme is mobile, with the 6α-hydroxyethyl group able to sample different orientations, while the water molecule necessary for deacylation is bound only transiently. These observations are consistent with the low level of meropenem turnover, supporting proposals that limited carbapenemase activity is a general property of OXA β-lactamases, and highlight the potential importance of OXA-57 in B. pseudomallei β-lactam resistance.

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Related topics: Antibiotic Resistance in Bacteria · Enzyme Structure and Function · Burkholderia infections and melioidosis