Molecular docking, dynamics and free energy analyses of Acinetobacter baumannii OXA class enzymes with carbapenems investigating their hydrolytic mechanisms

Balajee Ramachandran, Jeyaraman Jeyakanthan, Bruno S. Lopes

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Introduction. Acinetobacter baumannii is a critical priority pathogen listed by the World Health Organization due to increasing levels of resistance to carbapenem classes of antibiotics. It causes wound and other nosocomial infections, which can be life-threatening. Hence, there is an urgent need for the development of new classes of antibiotics. Aim. To study the interaction of carabapenems with class D beta-lactamases (oxacillinases) and analyse drug resistance by studying enzyme–substrate complexes using modelling approaches as a means of establishing correlations with the phenotypic data. Methodology. The three-dimensional structures of carbapenems (doripenem, ertapenem, imipenem and meropenem) were obtained from DrugBank and screened against class D beta-lactamases. Further, the study was extended with their variants. The variants’ structure was homology-modelled using the Schrödinger Prime module (Schrödinger LLC, NY, USA). Results. The first discovered intrinsic beta-lactamase of Acinetobacter baumannii, OXA-51, had a binding energy value of −40.984 kcal mol−1, whereas other OXA-51 variants, such as OXA-64, OXA-110 and OXA-111, have values of −60.638, –66.756 and −67.751 kcal mol−1, respectively. The free energy values of OXA-51 variants produced better results than those of other groups. Conclusions. Imipenem and meropenem showed MIC values of 2 and 8 µg ml−1, respectively against OXA-51 in earlier studies, indicating that these are the most effective drugs for treatment of A. baumannii infection. According to our results, OXA-51 is an active enzyme that shows better interactions and is capable of hydrolyzing carbapenems. When correlating the hydrogen-bonding interaction with MIC values, the predicted results are in good agreement and might provide initial insights into performing similar studies related to OXA variants or other antibiotic–enzyme-based studies.

Original languageEnglish
Pages (from-to)1062-1078
Number of pages17
JournalJournal of Medical Microbiology
Issue number8
Publication statusPublished - 10 Aug 2020

Bibliographical note

Funding Information:
B.R. and J.J. acknowledge financial supported from DST – FIST (SR/ FST/LSI-667/2016) (C), DST – Promotion of University Research and Scientific Excellence (PURSE) (no. SR/PURSE Phase2/38) (G), 2017, UGC-RA-(2016–18-OB-AM-7124 dated: 18.04.2016), DST-SERB (file no. EMR/2016/000498 dated: 26.09.2016), MHRD-RUSA 2.0, New Delhi [F.24-51/2014 U, Policy (TNMulti-Gen), Dept. of Edn. Govt. of India, Dt. 09.10.2018], DST Indo Taiwan project order no. (GITA/DST/TWN/P-86/2019 dated: 04/03/2020) and Alagappa University for providing computational facilities to carry out this work.

Publisher Copyright:
© 2020 The Authors


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