AUTHOR=Ramachandran Balajee , Muthupandian Saravanan , Jeyaraman Jeyakanthan , Lopes Bruno Silvester 

TITLE=Computational exploration of molecular flexibility and interaction of meropenem analogs with the active site of oxacillinase-23 in Acinetobacter baumannii

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2023.1090630

DOI=10.3389/fchem.2023.1090630

ISSN=2296-2646

ABSTRACT=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 analogues against OXA-23 positive Acinetobacter baumannii analysing the correlations between kinetic and phenotypic characteristics.
Methods: A total of 5450 compounds were screened by using Virtual Screening Workflow (HTVS, Glide-SP, 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 their analogues exhibited high level stable interactions with Ser79, Ser126, Thr217, Trp219, and Arg259 of OXA-23.  Meropenem displayed CovDock energy of about -3.5 and -1.9 kcal mol-1 against OXA-23 and OXA-27 respectively.  Among 5450 compounds, Pubchem_10645796, Pubchem_25224737, 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 1800 and 1125 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 MIC value is 32 μg ml−1 in OXA-23 positive isolate A2265 compared to MIC of 1 μg ml−1 in ΔblaOXA-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 its compliance with the phenotypic results. It will help further in developing newer antibiotics for treating severe infections associated with carbapenem resistant A. baumannii.