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

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Listed:
  • Elizabeth I. Parkinson

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Joseph S. Bair

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Bradley A. Nakamura

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Hyang Y. Lee

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Hani I. Kuttab

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Emma H. Southgate

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

  • Stéphane Lezmi

    (College of Veterinary Medicine, Veterinary Medicine Basic Sciences Building, University of Illinois at Urbana-Champaign)

  • Gee W. Lau

    (College of Veterinary Medicine, Veterinary Medicine Basic Sciences Building, University of Illinois at Urbana-Champaign)

  • Paul J. Hergenrother

    (Roger Adams Laboratory, University of Illinois at Urbana-Champaign)

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.

Suggested Citation

  • 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, 2015. "Deoxynybomycins inhibit mutant DNA gyrase and rescue mice infected with fluoroquinolone-resistant bacteria," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7947
    DOI: 10.1038/ncomms7947
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