ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Repurposing of FDA-approved drugs as potential inhibitors of L1 β-lactamase in Stenotrophomonas maltophilia

K. H. Sreenithya, Dhananjay Jade, and Shobana Sugumar

Department of Genetic Engineering, School of Bioengineering, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, India

E-mail: shobanas@srmist.edu.in

Received: 24 August 2024  Accepted: 13 March 2025

Abstract:

Antimicrobial resistance poses significant challenges, particularly with Stenotrophomonas maltophilia, a bacterium intrinsically resistant to antibiotics. This resistance is primarily attributed to the production of L1 β-lactamase, a metallo β-lactamase belonging to subclass B3 of the Ambler class enzymes. Chromosomally encoded, L1 β-lactamase hydrolyzes a broad spectrum of β-lactam antibiotics, including carbapenems, which are often considered the last-resort treatment for bacterial infections. The neutralization of many β-lactam antibiotics by this enzyme severely limits treatment options, making infections increasingly difficult to manage. To address this, research into specific inhibitors of L1 β-lactamase is gaining momentum, with the potential to pave the way for novel therapeutic agents targeting this enzyme. This study employs high-throughput virtual screening of FDA-approved drugs using AutoDock Vina, selecting the top 20 compounds based on the lowest binding energy. These compounds are further evaluated through ADMET, PAINS, density functional theory, and molecular dynamics simulations for 500 ns, followed by binding free energy examination using the MM/PBSA method. Through this in silico approach, two drug compounds, Dolutegravir (− 8.6 kcal/mol) and Lumacaftor (− 9.1 kcal/mol), are identified as potential inhibitors based on their binding energies. The complexes demonstrate stability throughout the 500 ns simulation. Dolutegravir (− 61.54 kJ/mol) exhibits stronger interaction with the protein compared to Lumacaftor (− 53.43 kJ/mol). These screened inhibitors open up possibilities for the development of combination therapies. Repurposing drugs offers a strategic advantage, as these compounds have already passed clinical safety tests, potentially reducing the cost and time required to bring new treatments to market.

Graphical abstract

Keywords: Antibiotics; Drug Therapy; Leukaemia Inhibitory Factor; Medicinal Chemistry; Phenotypic Drug Screening; Antibacterial drug resistance; Drug repurposing; Metallo β-lactamase; Stenotrophomonas maltophilia; DFT; Binding free energy; MD simulation

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-025-04046-z

Chemical Papers 79 (7) 4197–4212 (2025)