Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii.

ABSTRACT

Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme-DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance. Fluoroquinolones cause stepwise mutations in DNA gyrase and Topo IV, having alterations of their binding sites. Furthermore, the water-Mg+2 bridge, which provides enzyme-fluoroquinolone interactions, has a significant role in resistance. In this study, 13 compounds were synthesized as 1,4-benzoxazine derivatives which act as bacterial topoisomerase II inhibitors and their antibacterial activities were determined against multi-drug resistant Acinetobacter strains which have ciprofloxacin (CIP) resistant and GyrA mutation. Afterwards we performed docking studies with Topo IV (pdb2XKK) of these compounds to comprehend their binding properties in Discovery Studio 3.5. The results of this study show significant conclusions to elucidate the resistance mechanism and lead to the design of new antibacterial agents as bacterial topoisomerase II inhibitors.