Targeting Biofilm Formation in Acinetobacter baumannii: In Silico Discovery of Novel Candidate Inhibitors for...

Acinetobacter baumannii, a Gram-negative member of the ESKAPE pathogens, has emerged as a pivotal cause of multidrug-resistant hospital-acquired or nosocomial infections worldwide. Its ability to regulate virulence and biofilm formation through quorum sensing (QS) significantly contributes to its virulence and pathogenicity. Acyl-homoserine lactone synthase (AHLS) from the A. baumannii AYE strain plays a key role in the QS pathway and represents a promising druggable target for the development of anti-bacterial strategies.

A homology-modeled three-dimensional structure of AHLS (AYE strain) was predicted, optimized, and validated. High-throughput virtual screening of 975 natural antimicrobial compounds was performed, followed by Lipinski's and ADMET profiling to assess drug-likeness and safety. Promising drug candidates were further evaluated using 100ns molecular dynamics (MD) simulations to identify putative AHLS inhibitors.

MM/PBSA based binding free energy calculations revealed favorable interactions for CID_291096 (-14.74 ± 2.20 kcal/mol), CID_155586 (-15.26 ± 2.27 kcal/mol), and MSID_001127 (-28.44 ± 3.32 kcal/mol). Among these, MSID_001127 (Lovastatin) demonstrated superior structural stability and sustained intermolecular non-covalent interactions throughout the 100ns MD simulation. Structural stability was further supported by RMSD, RMSF, Rg, SASA, PCA, and hydrogen-bonding analyses.

Through virtual screening, three phytochemical lead compounds targeting AHLs with high negative binding free energies were identified. Stable protein-ligand interactions and favourable binding energetics were identified by molecular docking, 100 ns molecular dynamics simulations, and MM/PBSA analyses. Based on the results, ligand MSID_001127 was the most promising lead candidate compared with cipargamin. However, additional experimental validation is required to verify its therapeutic potential and biological activity.

These findings suggest that Lovastatin may be a promising drug candidate for AHLS targeting the QS pathway of A. baumannii. The results warrant further experimental validation to explore its potential as an anti-bacterial therapeutic agent.