title: 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.
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Parkinson
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bair
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Nakamura
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Hyang Y
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Hani I
authors.initials: HI
authors.lastname: Kuttab
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Emma H
authors.initials: EH
authors.lastname: Southgate
authors.affiliation: College of Veterinary Medicine, Veterinary Medicine Basic Sciences Building, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, Illinois 61802, USA.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lezmi
authors.affiliation: College of Veterinary Medicine, Veterinary Medicine Basic Sciences Building, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, Illinois 61802, USA.
authors.forename: Gee W
authors.initials: GW
authors.lastname: Lau
authors.affiliation: Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hergenrother
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D027081:DNA Gyrase / Q000235:genetics / Q000378:metabolism; D026942:DNA Topoisomerases / Q000235:genetics / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000201:enzymology; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013047:Specific Pathogen-Free Organisms; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D015363:Quinolones; C000605259:deoxynybomycin-2; C000605260:deoxynybomycin-3; C000874:deoxynybomycin; D026942:DNA Topoisomerases; D027081:DNA Gyrase