Structure-based functional fitness analyses of carbapenemase variants identified among pathogenic carbapenem-resistant G
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(2020) 36:129
ORIGINAL PAPER
Structure‑based functional fitness analyses of carbapenemase variants identified among pathogenic carbapenem‑resistant Gram‑negative bacteria Arijit Pal1 · Indrani Bhattacharyya2,3 · Anusri Tripathi1 Received: 30 March 2020 / Accepted: 19 July 2020 © Springer Nature B.V. 2020
Abstract 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 like blaNDM-1 (33.23%), blaNDM-1-like (0.31%), blaVIM-2 (4.35%), blaKPC-2 (4.04%), blaOXA-181 (6.85%), blaOXA-23 (16.50%), blaOXA-69 (3.88%), blaOXA-66 (2.91%) and blaOXA-104 (1.94%). Omega values indicated selection pressure over blaOXA-69, blaOXA-66 and blaOXA-104. Protein structural dynamics predicted NDM-1 and KPC-2 to have the highest and least flexibility, indicating differences in β-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. Keywords Carbapenem resistance · Carbapenemases · Bioinformatics · Selection pressure · Protein stability · Molecular docking
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11274-020-02905-3) contains supplementary material, which is available to authorized users. * Anusri Tripathi [email protected] 1
Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, 108, C.R. Avenue, Kolkata 700 073, India
2
Department of Microbiology, Calcutta School of Tropical Medicine, 108, C.R. Avenue, Kolkata 700 073, India
3
Present Address: Department of Microbiology, Calcutta National Medical College and Hospital, 32, Gorachand Road, Kolkata 700014, India
Ra
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