The β-lactamase of <i>Pseudomonas aeruginosa</i> is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum β-lactamase in a clinical isolate of <i>P. aeruginosa</i>, the bacterium has become multi-drug resistant. In this study, we aim to identify new β-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7-<i>O</i>-β-D-glucopyranoside (P7G) (-9.6 kcal/mol) from <i>Acacia pennata</i> and ellagic acid (EA) (-9.2 kcal/mol) from <i>Bridelia retusa</i> had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 (<i>Ser62, Asn125, Asn163, Thr209,</i> and <i>Ser230</i>) and 4 (<i>Lys65, Ser123, Asn125,</i> and <i>Glu159</i>) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with β-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of β-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of <i>A. pennata</i> as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the β-lactamase of <i>P. aeruginosa</i>.Communicated by Ramaswamy H. Sarma.
Authors: Abd. Kakhar Umar, Dhritiman Roy, Mohnad Abdalla, Yosra Modafer, Nawal Al‐Hoshani, Han Yu, James H. Zothantluanga
DOI: https://doi.org/10.1080/07391102.2023.2248272
Publish Year: 2023
