Evaluating Natural Compounds as Inhibitors of Lipopolysaccharide Biosynthesis in <i>Acinetobacter baumannii</i>: A Comprehensive Method Employing Molecular Docking and Dynamics Simulations

The increasing prevalence of antimicrobial resistance, particularly in Gram-negative bacteria such as Acinetobacter baumannii, demands new antibiotics as existing ones become increasingly ineffective. The production of lipopolysaccharide (LPS) is vital in Gram-negative bacteria, making it a promising target for antibiotic development. This study focuses on discovering antibiotics targeting the early-stage LpxA, LpxC and LpxH enzymes. These are crucial to lipid A biosynthesis in the Raetz pathway and are vital for bacterial survival and virulence. LpxA transfers an R-3-hydroxy acyl chain during lipid A biosynthesis, crucial for bacterial growth and potential antibiotic development. Inhibiting LpxC can impede bacterial growth and increase vulnerability to other antibiotics, whereas targeting LpxH is especially lethal due to the buildup of toxic lipid A intermediates. We identified promising compounds using high-throughput virtual screening of 374 compounds from ChemDiv with Schrodinger’s Extra Precision (XP) mode, followed by MM-GBSA analysis. Molecular Dynamics Simulations (MDS) over 100 ns using GROMACS confirmed the structural stability of these proteins with novel lead compound complexes. Compounds with ChemDiv IDs N039-0003 and N002-0028 showed strong binding to LpxA, N034-0001 and N023-0006 to LpxC and N025-0038 and N039-0020 to LpxH, with binding energies between −4.85 kcal/mol and −8.41 kcal/mol and total binding energies spanning from −31.06 kcal/mol to −53.87 KJ/mol. These findings suggest that these novel lead compounds inhibit the LpxA, LpxC and LpxH proteins and serve as new antibiotics against A. baumannii. However, additional in vitro and in vivo studies are needed to confirm the efficacy of these compounds.