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

Elizabeth I Parkinson,Gee W Lau,Hani I Kuttab,Stéphane Lezmi,Emma H Southgate,Paul J Hergenrother,Joseph S Bair,Bradley A Nakamura,Hyang Y Lee

doi:10.1038/ncomms7947

Elizabeth I Parkinson, Gee W Lau + Show 7 more

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https://doi.org/10.1038/ncomms7947

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Journal: Nature Communications	Publication Date: Apr 24, 2015
Citations: 37	License type: CC BY 4.0

Affiliation: University of Illinois 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.

Highlights

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing
Target-site mutation is the major contributor to FQR1,4, with high-level resistance observed in bacteria possessing key mutations in both GyrA and ParC4
Nybomycin (NM) is a natural product first identified from a culture of a streptomycete isolated from a Missouri soil sample and found to have antibacterial activity[27,28]

Summary

Introduction

Fluoroquinolones are one of the most commonly prescribed classes of antibiotics, but fluoroquinolone resistance (FQR) is widespread and increasing. 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. VRE and MRSA both harbour these target-site mutations, with point mutations in the quinolone resistance-determining region (QRDR) of the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV. These mutations alter residues important for the binding of FQs, resulting in an approximately tenfold decrease in binding affinity[11,12]. Using a DNM derivative with superior solubility and pharmacokinetic properties, the first in-vivo activity of this class of compounds is demonstrated

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