Abstract
Background: Carbapenem-resistant Acinetobacter baumannii is an opportunistic pathogen responsible for nosocomial infections and is one of the biggest global threats according to the World Health Organization (WHO), particularly causing substantial morbidity and mortality. Objectives: This study aimed at using computational approaches to screen meropenem and its analogs against OXA-23-positive Acinetobacter baumannii, analyzing the correlations between kinetic and phenotypic characteristics. Methods: A total of 5,450 compounds were screened using virtual screening workflow (HTVS, Glide-SP, and Glide-XP) to identify the best compounds based on their binding energy and interactions against OXA-23 and OXA-27 as they had phenotypic data available. Molecular dynamics simulation and density functional theory (DFT) studies were performed from the outcome of molecular docking analysis. Results: During simulations, meropenem and its analogs exhibited high-level stable interactions with Ser79, Ser126, Thr217, Trp219, and Arg259 of OXA-23. Meropenem displayed a CovDock energy of about -3.5 and -1.9 kcal mol -1 against OXA-23 and OXA-27, respectively. Among the 5,450 compounds, Pubchem_10645796, Pubchem_25224737, and ChEMBL_14 recorded CovDock energy between -6.0 and -9.0 kcal mol -1. Moreover, the infra-red (IR) spectrophotometric analysis revealed C=O and C-N atoms showing bands at 1,800 and 1,125 cm -1, respectively. These observed data are in congruence with the experimental observations. Conclusion: The identified compounds showed good agreement with the spectrophotometric analysis using DFT methods. In the earlier studies, meropenem's MIC value was 32 μg mL -1 in OXA-23-positive isolate A2265 compared to the MIC of 1 μg mL -1 in Δ bla OXA-23 A2265. Comparing the CovDock energy and hydrogen-bonding interactions, the predicted results are in good agreement with the experimental data reported earlier. Our results highlight the importance of OXA-23 molecular docking studies and their compliance with the phenotypic results. It will help further in developing newer antibiotics for treating severe infections associated with carbapenem-resistant A. baumannii.
| Original language | English |
|---|---|
| Article number | 1090630 |
| Journal | Frontiers in Chemistry |
| Volume | 11 |
| DOIs | |
| Publication status | Published - 23 Feb 2023 |
Bibliographical note
Funding Information:JJ acknowledges financial support and infrastructure provided by DST INDO-TAIWAN (GITA/DST/TWN/P-86/2019), Department of Biotechnology, Bioinformatics Centre (BIC)—No. BT/PR40154/BTIS/137/34/2021, TANSCHE (RGP/2019- 20/ALU/HECP-0049 dated: 27/04/2021), DST-Fund for Improvement of S&T Infrastructure in Universities and Higher Educational Institutions (FIST) (SR/FST/LSI-667/2016) (C), and DST-Promotion of University Research and Scientific Excellence (PURSE phase II) (SR/PURSE Phase 2/38 (G), 2017), MHRD-RUSA 2.0, New Delhi (F.24e51/2014-U, Policy (TNMulti-Gen), for providing computational facilities to carry out this work. BL would like to acknowledge the School of Health and Life Sciences, Teesside University, for their kind support in covering the 20% APC.
Funding Information:
JJ acknowledges financial support and infrastructure provided by DST INDO-TAIWAN (GITA/DST/TWN/P-86/2019), Department of Biotechnology, Bioinformatics Centre (BIC)—No. BT/PR40154/BTIS/137/34/2021, TANSCHE (RGP/2019- 20/ALU/HECP-0049 dated: 27/04/2021), DST-Fund for Improvement of S&T Infrastructure in Universities and Higher Educational Institutions (FIST) (SR/FST/LSI-667/2016) (C), and DST-Promotion of University Research and Scientific Excellence (PURSE phase II) (SR/PURSE Phase 2/38 (G), 2017), MHRD-RUSA 2.0, New Delhi (F.24e51/2014-U, Policy (TNMulti-Gen), for providing computational facilities to carry out this work. BL would like to acknowledge the School of Health and Life Sciences, Teesside University, for their kind support in covering the 20% APC.
Publisher Copyright:
Copyright © 2023 Ramachandran, Muthupandian, Jeyaraman and Lopes.