Structure-based identification of novel inhibitors targeting the enoyl-ACP reductase enzyme of Acinetobacter baumannii

Acinetobacter baumannii is a Gram-negative multidrug-resistant bacterial pathogen primarily associated with nosocomial infections resulting in increased morbidity and mortality in adults and infants, especially in sub-Saharan Africa where the clinical burden is high. New therapeutics are needed to treat multidrug-resistant Acinetobacter baumannii infections and reduce transmission. The study used computer-integrated drug discovery approaches including pharmacophore modelling, molecular docking, and molecular dynamics simulation to screen potential inhibitors against the enoyl-acyl carrier protein reductase-FabI protein of Acinetobacter baumannii. The top three potential inhibitors: 21272541 > 89795992 > 89792657 showed favourable binding free energies including coulombic energy, van der Waals energy, and polar and non-polar energies. Furthermore, all three complexes were extremely stable and compact with reduced fluctuations during the simulations period. Inhibitor 21272541 exhibited the highest binding affinity against the Acinetobacter baumannii FabI protein. This is similar to our recent report, which also identified 21272541 as the lead inhibitor against Klebsiella pneumoniae infections. Future clinical studies evaluating drug effectiveness should prioritise inhibitor 21272541 which could be effective in treating infections caused by Gram-negative organisms.