Structural interactions of BWC0977 with Klebsiella pneumoniae topoisomerase IV and biochemical basis of its broad-spectrum activity.

ABSTRACT: Antimicrobial resistance is a growing global health crisis driving the urgent need for effective broad-spectrum antibiotics. BWC0977 is a pyrazino-oxazinone based novel bacterial topoisomerase inhibitor (NBTI) currently in Phase 1 clinical trials and demonstrates potent activity against multidrug-resistant Gram-negative and Gram-positive bacteria. It targets both DNA gyrase and topoisomerase IV with balanced low-nanomolar potencies, showing remarkable superiority over ciprofloxacin and gepotidacin. We report the first 3.05 Å cocrystal structure of BWC0977 bound to Klebsiella pneumoniae topoisomerase IV, revealing its binding mode and interaction residues. The reduced inhibition of BWC0977 against purified gyrase enzymes carrying an individual mutation at these residues supports the relevan

SUBMITTER: Nandishaiah R 

PROVIDER: S-EPMC12647645 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature