Beschreibung:
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>Staphylococcus aureus</jats:italic> and vancomycin-resistant <jats:italic>Enterococci</jats:italic> clinical isolates and inhibit mutant DNA gyrase <jats:italic>in-vitro</jats:italic>. 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 <jats:italic>in-vivo</jats:italic> 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.</jats:p>