Integrated Bioprospection of Phenolics as Potent Modulators of Acinetobacter baumannii Penicillin‐Binding Protein 1A

Diseases caused by carbapenem‐resistant Acinetobacter baumannii can lead to death within 48 h of hospitalization, with an overall mortality rate of 68%. The reduced affinity of carbapenem and other β‐lactams for penicillin‐binding proteins 1A (PBP1A), a critical protein, is a key resistance mechanism in A. baumannii . PBP1A is essential for the formation, division, and maintenance of homeostasis and proper growth in A. baumannii , making it an important therapeutic target. In this study, a structure‐activity relationship approach, supported by molecular docking, was used to screen 12,000 phenolics for their affinity for PBP1A of A. baumannii . The top five phenolics, with the most negative docking scores and favorable drug‐like properties compared to the reference antibiotic (imipenem), were further analyzed using a 300,000‐ps molecular dynamics (MD) simulation. The results showed that the leading phenolics (ZINC12659587 at −25.20 kcal/mol, ZINC59466627 at −35.01 kcal/mol, ZINC04989868 at −19.67 kcal/mol, ZINC71285349 at −17.90 kcal/mol, and ZINC58836805 at −11.95 kcal/mol) had better affinity for PBP1A and were more compact (28.20–29.87 Å) than imipenem (−11.50 kcal/mol and 29.97 Å). Compared to the unbound protein (2.89 Å), the top five phenolics were more stable (2.28–2.76 Å), except ZINC12659587 (4.41 Å), while ZINC59466627 is the most effective and compact. Additionally, except for ZINC12659587, quantum calculations using DFT B3LYP/6‐31G+ (dp) indicated that the top five leads are more reactive than imipenem. These findings provide scientific credence to the profiled phenolics, especially ZINC59466627, as modulators of PBP1A in A. baumannii and may have therapeutic implications for managing ventilator‐associated pneumonia and bloodstream infections. Further validation through in vitro and in vivo studies will be conducted to confirm the exact mechanisms of action of the identified compounds.