Parkinson Elizabeth I, Bair Joseph S, Nakamura Bradley A, Lee Hyang Y, Kuttab Hani I, Southgate Emma H, Lezmi Stéphane, Lau Gee W, Hergenrother Paul J
Roger Adams Laboratory, Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801, USA.
College of Veterinary Medicine, Veterinary Medicine Basic Sciences Building, University of Illinois at Urbana-Champaign, 2001 South Lincoln Avenue, Urbana, Illinois 61802, USA.
Nat Commun. 2015 Apr 24;6:6947. doi: 10.1038/ncomms7947.
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.
氟喹诺酮类是最常用的抗生素类别之一，但氟喹诺酮耐药性（FQR）广泛存在且呈上升趋势。脱氧尼博霉素（DNM）是一种具有独特作用机制的天然产物抗生素，可抑制赋予FQR的突变型DNA旋转酶。不幸的是，DNM的分离困难，且DNM不溶于水溶液，这使其成为开发的不佳候选物。在此，我们描述了一种简便的化学路线来生产DNM及其衍生物。这些化合物对FQR耐甲氧西林金黄色葡萄球菌和耐万古霉素肠球菌临床分离株具有优异的活性，并在体外抑制突变型DNA旋转酶。对DNM产生耐药性的细菌对氟喹诺酮类重新敏感，这表明对DNM产生的耐药性是可治疗的。使用一种DNM衍生物，在小鼠感染模型中证明了尼博霉素类的首次体内疗效。总体而言，所呈现的数据表明DNM衍生物在治疗FQR感染方面具有前景。
