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The Natural Product Corramycin Acts as a DNA Gyrase Poison and Overcomes Fluoroquinolone Resistance in Mycobacterium tuberculosis
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DOI：10.1002/advs.76832.png)
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Abstract
En 中文
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.
Keywords:
cryo-EM
DNA synthesis inhibitor
gyrase poison
mechanism of action
Mycobacterium tuberculosis
natural products
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