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Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum β-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa

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Abstract

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic bacterium that frequently causes nosocomial infections. New generation cephalosporins and β-lactams along with inhibitors are used for the treatment of opportunistic bacterial infections. The indiscriminate use of antibiotics has led to the emergence of bacterial resistance. Carbapenem class of antibiotics like imipenem and meropenem are currently the final line of antibiotics for the treatment of infections caused by multidrug-resistant P. aeruginosa. Recent reports indicate that P. aeruginosa has acquired resistance to imipenem through a class D oxacillinase—OXA-10 extended spectrum β-lactamase (ESBL). OXA-10 ESBL is encoded by the gene blaOXA-10. There is an urgent need to develop OXA-10 ESBL non-hydrolysing inhibitors. We have attempted to locate OXA-10 ESBL inhibitors by performing molecular docking and molecular dynamics studies on OXA-10 ESBL with imipenem analogues from ZINC database as well as employing imipenem to understand the mechanism of resistance at the structural level. Our in-silico analysis of imipenem analogues reveals that ZINC44672480 has ideal characteristics for a potent OXA-10 ESBL non-hydrolysing inhibitor. We believe that the results from our study will provide valuable insights into the mechanism of drug resistance and aid in designing potent inhibitors against OXA-10 ESBL producing P. aeruginosa.

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Abbreviations

ESBL:

Extended spectrum β-lactamase

OXA:

Oxacillinase

PDB:

Protein data bank

C-score:

Consensus score

MD:

Molecular dynamics

PASS:

Prediction of activity spectra for substances

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

Rg:

Radius of gyration

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Acknowledgments

SR gratefully acknowledges the Indian Council of Medical Research (ICMR), Government of India Agency for the research Grant (IRIS ID: 2014-0099). The authors would also like to thank the management of VIT University for providing the necessary facilities to carry out this research project.

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  1. Medical & Biological Computing Laboratory, Department of Biosciences, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, 632014, India

    Kullappan Malathi & Sudha Ramaiah

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  1. Kullappan Malathi
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Correspondence to Sudha Ramaiah.

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Malathi, K., Ramaiah, S. Molecular Docking and Molecular Dynamics Studies to Identify Potential OXA-10 Extended Spectrum β-Lactamase Non-hydrolysing Inhibitors for Pseudomonas aeruginosa . Cell Biochem Biophys 74, 141–155 (2016). https://doi.org/10.1007/s12013-016-0735-8

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