Network Analysis of polA in Acinetobacter baumannii International Clone 2 and Computational Evaluation of Nodulisporone and Nodulisporol as Potential Inhibitors

Acinetobacter baumannii is a Gram-negative opportunistic pathogen linked to over 400,000 deaths annually, with International Clone 2 (IC2) recognised as a major multidrug-resistant (MDR) lineage. We analysed 668 IC2 genomes from BIGSdb, assessed completeness using usegalaxy-BUSCO, and annotated them with Prokka. Protein-protein interactions were mapped using STRING; interacting genes were identified using Cytoscape; functional enrichment was conducted using Enrichr and KEGG, retrieving protein from UniProt; and potential drug candidates were obtained from ChEMBL. Molecular docking was carried out using Autodock 4, and the complexes were visualised in Discovery studio. ADME profiling with SWISSADME and toxicity were assessed using MCULE and ProTOX-3.0. We identified polA as a major hub gene involved in DNA repair and essential for survival under genotoxic antibiotic stress, suggesting that it could impair bacterial adaptability and resistance mechanisms. Molecular docking using AutoDock Vina identified Nodulisporone and Nodulisporol from ChEMBL as potential inhibitors that also fulfilled Lipinski's criteria, with higher binding affinities for A. baumannii PolA than for human DNA polymerase lambda (PolL). This suggests that polA inhibition may potentiate existing antibiotics, reducing the dissemination of resistance and disrupting essential repair processes. Our bioinformatic and computational biology approach offers an effective strategy for developing novel treatments against multidrug-resistant pathogens.