Determination of potential combination of non‐β‐lactam, β‐lactam, and β‐lactamase inhibitors/β‐lactam enhancer against class D oxacillinases producing Acinetobacter baumannii: Evidence from in‐vitro, molecular docking and dynamics simulation

Author:

Gopikrishnan Mohanraj1ORCID,Ramireddy Sriroopreddy1ORCID,Varghese Rinku Polachirakkal1ORCID,Bakathavatchalam Yamuna Devi2,D Thirumal Kumar3ORCID,Manesh Abi4,Walia Kamini5,Veeraraghavan Balaji2ORCID,C George Priya Doss1ORCID

Affiliation:

1. Department of Integrative Biology, School of Biosciences and Technology VIT Vellore Tamil Nadu India

2. Department of Clinical Microbiology Christian Medical College Vellore Tamil Nadu India

3. Meenakshi Academy of Higher Education and Research Chennai Tamil Nadu India

4. Department of Infectious Disease Christian Medical College Vellore Tamil Nadu India

5. Division of Epidemiology & Communicable Diseases Indian Council of Medical Research New Delhi India

Abstract

AbstractCarbapenem‐resistant Acinetobacter baumannii, a predominant nosocomial pathogen in hospitals of intensive care units, is associated with bacteremia and ventilator‐associated pneumonia with a high‐risk mortality rate. To increase the effectiveness of the β‐lactam (BL) antibiotics, the use of β‐lactamase inhibitors (BLI) acts as a booster when given in combination with BL antibiotics. To this aspect, we selected BL antibiotics of cefiderocol, cefepime, non‐BL antibiotic eravacycline, BLI of durlobactam, avibactam, and a β‐lactam enhancer (BLE) of zidebactam. To prove our hypothesis, we determined the minimum inhibitory concentration (MIC) of various BL or non‐BL/BLI or BLE combinations using broth microdilution method followed by in silico analysis of molecular docking, molecular dynamics (MD) simulation, and molecular mechanics Poisson–Boltzmann surface area (MM‐PBSA) identifies the potential combination. In MIC testing, eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with zidebactam or durlobactam were found to be effective against oxacillinases (OXAs) (OXA‐23/24/58 like) expressing A. baumannii isolates. The docking results of the selected ligands toward OXA‐23, OXA‐24, and OXA‐58 had an excellent binding score ranging from −5.8 to −9.3 kcal/mol. Further, the docked complexes were subjected and evaluated using gromacs for molecular dynamics simulation of 50 ns toward selected class D OXAs. The binding energies obtained from MM‐PBSA shed light on the binding efficiencies of each non‐BL, BL, and BLI/BLE, thereby helping us to propose the drug combinations. Based on the MD trajectories scoring acquired, we propose using eravacycline, cefepime/zidebactam, cefiderocol/zidebactam, and eravacycline in combination with durlobactam or zidebactam would be promising for treating OXA‐23, OXA‐24, and OXA‐58 like expressing A. baumannii infections.

Funder

Indian Council of Medical Research

Publisher

Wiley

Subject

Cell Biology,Molecular Biology,Biochemistry

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