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

Elizabeth 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number6947
JournalNature communications
Volume6
DOIs
StatePublished - Apr 22 2015

Fingerprint

DNA Gyrase
Fluoroquinolones
bacteria
mice
Bacteria
deoxyribonucleic acid
antibiotics
infectious diseases
Derivatives
staphylococcus
Anti-Bacterial Agents
Methicillin
deoxynybomycin
isolation
Vancomycin
Methicillin-Resistant Staphylococcus aureus
Microbial Drug Resistance
Infection
Biological Products
routes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria. / Parkinson, Elizabeth I.; Bair, Joseph S.; Nakamura, Bradley A.; Lee, Hyang Y.; Kuttab, Hani I.; Southgate, Emma H.; Lezmi, Stéphane; Lau, Gee W.; Hergenrother, Paul J.

In: Nature communications, Vol. 6, 6947, 22.04.2015.

Research output: Contribution to journalArticle

Parkinson, Elizabeth I. ; Bair, Joseph S. ; Nakamura, Bradley A. ; Lee, Hyang Y. ; Kuttab, Hani I. ; Southgate, Emma H. ; Lezmi, Stéphane ; Lau, Gee W. ; Hergenrother, Paul J. / Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria. In: Nature communications. 2015 ; Vol. 6.
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