Exploring imidazo[4,5-g]quinoline-4,9-dione derivatives as Acinetobacter baumannii efflux pump inhibitor: an in silico approach

Abstract

Antimicrobial resistance (AMR) is fast becoming a medical crisis affecting the entire global population. World Health Organization (WHO) statistics show that globally 0.7 million people are dying yearly due to the emergence of AMR. By 2050, the expected number of lives lost will be 10 million per year. Acinetobacter baumannii is a dreadful nosocomial pathogen that has developed multidrug resistance (MDR) to several currently prescribed antibiotics worldwide. Overexpression of drug efflux transporters (DETs) is one of the mechanisms of multidrug resistance (MDR) in Acinetobacter baumannii. Therefore, blocking the DET can raise the efficacy of the existing antibiotics by increasing their residence time inside the bacteria. In silico screening of five synthetic compounds against three drug efflux pump from A. baumannii has identified KSA5, a novel imidazo[4,5-g]quinoline-4,9-dione derivative, to block the efflux of antibiotics. Molecular docking and simulation results showed that KSA5 could bind to adeB, adeG, and adeJ by consistently interacting with ligand-binding site residues. KSA5 has a higher binding free energy and a lower HOMO-LUMO energy gap than PAβN, suggesting a better ability to interact and inhibit DETs. Further analysis showed that KSA5 is a drug-like molecule with optimal physicochemical and ADME properties. Hence, KSA5 could be combined with antibiotics to overcome antimicrobial resistance.

Communicated by Ramaswamy H. Sarma

Keywords:

• Acinetobacter baumannii
• multidrug resistance
• efflux pump inhibitor
• imidazo[4
• 5-g]quinoline-4
• 9-dione derivatives and in silico

Acknowledgments

BGP thanks UGC non-NET fellowship and the Department of Bioinformatics, Pondicherry University, for the computational facilities to carry out this work. BGP also thank Mr. Satya Ranjan Singh, Mr. Karamveer, Mr. Pranavathiyani G, Dr. Manikandan Jayaraman and Dr. Guneswar Sethi for their valuable suggestions. KS (EMR/2015/000466A) thanks to the financial support from the Science and Engineering Research Board, Department of Science and Technology, India. KS thanks Vellore Institute of Technology, Vellore, for the Seed Grant-SG20210103. Also, the authors thank Dr. R. Padmanaban and Mr. Thamarainathan Doulassiramane, Dept. Chemistry, Pondicherry University, for providing the DFT calculations.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

BGP: Methodology, Visualization, Data Analysis, Original Draft Writing and Editing. KA and KS: Compound Design and Writing. SMC: Conceptualization, Data Analysis, Draft Review/Editing, and Project Supervision.

Data availability statement

The data is available with the authors and shall be provided upon request.

Additional information

Funding

KS [EMR/2015/000466A & Seed Grant-SG20210103] received financial support from the Science and Engineering Research Board, Department of Science and Technology, India and Vellore Institute of Technology, Vellore, India.