The Natural Product Corramycin Acts as a DNA Gyrase Poison and Overcomes Fluoroquinolone Resistance in Mycobacterium tuberculosis
Abstract
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.
Read the paper
Related studies
- Horizontal gene transfer in the human gastrointestinal tract: potential spread of antibiotic resistance genes
- Mutation supply and relative fitness shape the genotypes of ciprofloxacin-resistant Escherichia coli
- Genomic Survey of E. coli From the Bladders of Women With and Without Lower Urinary Tract Symptoms
- Characterization of cefotaxime-resistant urinary Escherichia coli from primary care in South-West England 2017–18
- Fitness cost constrains the spectrum of marR mutations in ciprofloxacin-resistant Escherichia coli
- Emerging evidence-based innovative approaches to control catheter-associated urinary tract infection: a review
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.