Abstract
OXA-48-producing Enterobacterales have now widely disseminated globally. A sign of their extensive spread is the identification of an increasing number of OXA-48 variants. Among them, three are particularly interesting, OXA-163, OXA-247 and OXA-405, since they have lost carbapenem activities and gained expanded-spectrum cephalosporin hydrolytic activity subsequent to a four amino-acid (AA) deletion in the β5–β6 loop. We investigated the mechanisms responsible for substrate specificity of OXA-405. Kinetic parameters confirmed that OXA-405 has a hydrolytic profile compatible with an ESBL (hydrolysis of expanded spectrum cephalosporins and susceptibility to class A inhibitors). Molecular modeling techniques and 3D structure determination show that the overall dimeric structure of OXA-405 is very similar to that of OXA-48, except for the β5–β6 loop, which is shorter for OXA-405, suggesting that the length of the β5–β6 loop is critical for substrate specificity. Covalent docking with selected substrates and molecular dynamics simulations evidenced the structural changes induced by substrate binding, as well as the distribution of water molecules in the active site and their role in substrate hydrolysis. All this data may represent the structural basis for the design of new and efficient class D inhibitors.
Highlights
The widespread use of antibiotics led to the emergence of carbapenem resistance in Gram-negative bacteria and became a real clinical concern
Kinetic parameters confirmed that OXA-405 behaves more like an ESBL ß-lactamase, rather than a carbapenemase
Molecular modeling techniques and 3D structure determination show that the overall dimeric structure of OXA-405 is very similar to that of OXA-48, except for the β5–β6 loop, which is shorter for OXA-405, suggesting that the length of the β5–β6 loop is critical for substrate specificity
Summary
The widespread use of antibiotics led to the emergence of carbapenem resistance in Gram-negative bacteria and became a real clinical concern. This resistance is mostly due to the production of carbapenem-hydrolyzing β-lactamases, carbapenemases that belong to Amber class A (KPC), B (NDM, VIM, and IMP), or D (OXA-48 and its variants) [1]. When associated to impaired outer-membrane permeability and an ESBL, OXA-48-producers may turn. Microorganisms 2020, 8, 24 when associated to impaired outer-membrane permeability and an ESBL, OXA-48-producers may turn into deadly bacteria, only limited antibiotic for treating infections with into deadly bacteria, as onlyaslimited antibiotic choiceschoices are leftare forleft treating seriousserious infections with these these bacteria [5]. Microorganisms 2020, 8, 24 when associated to impaired outer-membrane permeability and an ESBL, OXA-48-producers may turn into deadly bacteria, only limited antibiotic for treating infections with into deadly bacteria, as onlyaslimited antibiotic choiceschoices are leftare forleft treating seriousserious infections with these these bacteria [5]. bacteria [5].
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