4.5 Article

Structure-based functional fitness analyses of carbapenemase variants identified among pathogenic carbapenem-resistant Gram-negative bacteria

Journal

Publisher

SPRINGER
DOI: 10.1007/s11274-020-02905-3

Keywords

Carbapenem resistance; Carbapenemases; Bioinformatics; Selection pressure; Protein stability; Molecular docking

Funding

  1. Indian Council of Medical Research [3/1/3/WL/JRF-2011/HRD-129 (41937)]

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Carbapenemase-mediated carbapenem resistance is a major public health concerns worldwide. In the present study, prevalence of circulating carbapenemases was estimated among carbapenem-resistant clinical isolates using PCR and sequencing. Diameters of zone of inhibition (ZDs) were compared for imipenem, meropenem and ertapenem among single carbapenemase producing isolates. Structure-based functional fitness of those carbapenemases was predicted through several in silico analyses. Approximately, 63.76% isolates demonstrated carbapenem resistance, of which 39.13% harboured carbapenemases likebla(NDM-1)(33.23%),bla(NDM-1)-like (0.31%),bla(VIM-2)(4.35%),bla(KPC-2)(4.04%),bla(OXA-181)(6.85%),bla(OXA-23)(16.50%),bla(OXA-69)(3.88%),bla(OXA-66)(2.91%) andbla(OXA-104)(1.94%). Omega values indicated selection pressure overbla(OXA-69),bla(OXA-66)andbla(OXA-104). Protein structural dynamics predicted NDM-1 and KPC-2 to have the highest and least flexibility, indicating differences in beta-lactam binding and catalytic efficiency. Increased requirement of free folding energy, improved solvent accessibility and decreased melting temperatures among NDM-1-like, OXA-181, OXA-66, OXA-69 and OXA-104 predicted functional improvement over their ancestral variants. NDM-1-like carbapenemases demonstrated improvement in binding stability, affinity and catalysis of meropenem than that of NDM-1. Catalytic activity of imipenem was predicted to improve among OXA-181, which could be correlated with more than 1.5 folds smaller ZDs around imipenem disc, than that of meropenem/ertapenem, among OXA-181 producing isolates. However, OXA-66 indicated greater binding stability and affinity for imipenem and meropenem. This study indicated structural/functional convergence as well as divergence among several carbapenemase variants and provided useful insights into carbapenemase-mediated carbapenem resistance that might help in identifying appropriate treatment regimen for bacterial infections.

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