Unraveling the Bifunctional HisIE Enzyme in Acinetobacter baumannii JJAB01: A Novel Therapeutic Target for Combating Antimicrobial Resistance.

Antimicrobial resistance (AMR) in ESKAPE pathogens presents a critical global health challenge, particularly in hospitals. The enzyme HisIE from A. baumannii was explored as a therapeutic target using structure-based drug design to combat bacterial infections. This study integrates various computational approaches, including homology modeling, molecular dynamics simulations (MDS), and structure-based virtual screening to identify the potent inhibitors with high binding affinity and favorable pharmacokinetic properties. High-throughput virtual screening of the COCONUT database identified lead compounds featuring strong binding affinities to protein targets along with favorable pharmacokinetic profiles. CNP0007442, CNP0007145, and CNP0007506 emerged as the most potent candidates based on MM/GBSA binding free energy calculations. They exhibited stable interactions with key active site residues (His98) of AbHisIE, primarily through Van der Waals and electrostatic forces, enabling enhanced enzyme inhibition. Furthermore, density functional theory analysis revealed optimal HOMO-LUMO energy gaps, indicating the selected compounds' potential reactivity and stability. The findings highlight these candidates for further experimental validation, offering a novel therapeutic approach by disrupting the essential bacterial metabolic pathways. This study identifies promising drug-like molecules targeting AbHisIE, offering a novel strategy to combat AMR infections.