Article

Rationale and design of an inhibitor of RecA protein as an inhibitor of Acinetobacter baumannii

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Abstract

Acinetobacter baumannii is one of the ESKAPE pathogen, which causes pneumonia, urinary tract infections, and is linked to high degree of morbidity and mortality. One-way antibiotic and disinfectant resistance is acquired by the activation of RecA-mediated DNA repair (SOS-response) that maintain ROS-dependent DNA damage caused by these anti-bacterial molecules. To increase the efficacy of different anti-microbial, there is a need to design an inhibitor against RecA of A. baumannii. We have performed homology modeling to generate the structure of RecA, followed by model refinement and validation. High-throughput virtual screening of 1,80,313 primary and secondary metabolites against RecA was performed in HTVS, SP, and XP docking modes. The selected 195 compounds were further analyzed for binding free energy by molecular mechanics approach. The selected top two molecules from molecular mechanics approach were further validated by molecular dynamics simulation (MDS). In-silico high-throughput virtual screening and MDS validation identified ZINC01530654 or  (+−)-2-((4-((7-Chloro-4-quinolyl)amino)pentyl)ethylamino)ethanol sulfate (or hydroxychloroquine sulfate) as a possible lead molecule binding to RecA protein. We have experimentally determined the mechanism of ZINC01530654 to RecA protein. These findings suggest a strategy to chemically inhibit the vital process controlled by RecA that could be helpful for the development of new antibacterial agents.

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Acknowledgements

VT thanks SERB, DST, India for Start Up grant (SB/YS/LS-07/2014). MT thanks Central University of Rajasthan for Ph.D. fellowship.

Author information

Affiliations

  1. Department of Biochemistry, Central University of Rajasthan, Bandarsindri, Ajmer, 305817, India

    • Vishvanath Tiwari
    • , Monalisa Tiwari
    •  & Deepika Biswas

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Contributions

VT conceived and designed the experiments, performed the experiments (in-silico modeling and drug designing, MDS, and ROS estimation for imipenem), and analysed the data. MT performed experimental validation of lead. DB performed ROS estimation for disinfectants. VT wrote the manuscript. MT and VT proofread the final version.

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Vishvanath Tiwari.

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