The Natural Product Corramycin Acts as a DNA Gyrase Poison and Overcomes Fluoroquinolone Resistance in Mycobacterium tuberculosis.

Despite significant advancements in drug development and discovery, tuberculosis remains one of the world's deadliest infectious diseases. The rise and global spread of multidrug-resistant strains underscore a critical need for new antibiotics with distinct mechanisms of action. Screening of a myxobacterial extract library uncovered the previously unrecognized antitubercular activity of corramycin, a natural product with potent bactericidal activity against both drug-sensitive and -resistant Mycobacterium tuberculosis. Corramycin enters the bacterial cell by exploiting multiple transport systems, and induces DNA double-strand breaks through a novel form of DNA gyrase poisoning. The cryo-electron microscopy structure of M. tuberculosis gyrase in complex with corramycin reveals that the natural product targets a site overlapping with the binding site of synthetic fluoroquinolones, thereby locking the gyrase in an inactive conformation and preventing re-ligation of DNA. Importantly, its unique mode of binding allows corramycin to overcome fluoroquinolone resistance, highlighting its promise as a novel antibiotic scaffold to address the antimicrobial resistance crisis.