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 and Paul J. Hergenrother ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-9

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7947

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