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Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria.

Abstract
Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. Deoxynybomycin (DNM) is a natural-product antibiotic with an unusual mechanism of action, inhibiting the mutant DNA gyrase that confers FQR. Unfortunately, isolation of DNM is difficult and DNM is insoluble in aqueous solutions, making it a poor candidate for development. Here we describe a facile chemical route to produce DNM and its derivatives. These compounds possess excellent activity against FQR methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci clinical isolates and inhibit mutant DNA gyrase in-vitro. Bacteria that develop resistance to DNM are re-sensitized to fluoroquinolones, suggesting that resistance that emerges to DNM would be treatable. Using a DNM derivative, the first in-vivo efficacy of the nybomycin class is demonstrated in a mouse infection model. Overall, the data presented suggest the promise of DNM derivatives for the treatment of FQR infections.
AuthorsElizabeth I Parkinson, Joseph S Bair, Bradley A Nakamura, Hyang Y Lee, Hani I Kuttab, Emma H Southgate, Stéphane Lezmi, Gee W Lau, Paul J Hergenrother
JournalNature communications (Nat Commun) Vol. 6 Pg. 6947 (Apr 24 2015) ISSN: 2041-1723 [Electronic] England
PMID25907309 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Bacterial Agents
  • Fluoroquinolones
  • Quinolones
  • deoxynybomycin-2
  • deoxynybomycin-3
  • deoxynybomycin
  • DNA Topoisomerases
  • DNA Gyrase
Topics
  • Animals
  • Anti-Bacterial Agents (chemistry, pharmacology, therapeutic use)
  • DNA Gyrase (genetics, metabolism)
  • DNA Topoisomerases (genetics, metabolism)
  • Drug Resistance, Bacterial
  • Escherichia coli (enzymology)
  • Female
  • Fluoroquinolones (pharmacology)
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mutagenesis, Site-Directed
  • Quinolones (chemistry, pharmacology, therapeutic use)
  • Specific Pathogen-Free Organisms
  • Staphylococcal Infections (drug therapy, microbiology)
  • Staphylococcus aureus (drug effects)

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