State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, China.
Nat Chem Biol. 2016 Mar;12(3):174-9. doi: 10.1038/nchembio.2003. Epub 2016 Jan 18.
The surge of antibiotic resistance in Staphylococcus aureus has created a dire need for innovative anti-infective agents that attack new targets, to overcome resistance. In S. aureus, carotenoid pigment is an important virulence factor because it shields the bacterium from host oxidant killing. Here we show that naftifine, a US Food and Drug Administration (FDA)-approved antifungal drug, blocks biosynthesis of carotenoid pigment at nanomolar concentrations. This effect is mediated by competitive inhibition of S. aureus diapophytoene desaturase (CrtN), an essential enzyme for carotenoid pigment synthesis. We found that naftifine attenuated the virulence of a variety of clinical S. aureus isolates, including methicillin-resistant S. aureus (MRSA) strains, in mouse infection models. Specifically, we determined that naftifine is a lead compound for potent CrtN inhibitors. In sum, these findings reveal that naftifine could serve as a chemical probe to manipulate CrtN activity, providing proof of concept that CrtN is a druggable target against S. aureus infections.
金黄色葡萄球菌对抗生素耐药性的激增，使得我们迫切需要创新的抗感染药物来对抗新的靶点，以克服耐药性。在金黄色葡萄球菌中，类胡萝卜素色素是一种重要的毒力因子，因为它可以保护细菌免受宿主氧化剂的杀伤。在这里，我们发现，美国食品和药物管理局（FDA）批准的抗真菌药物萘替芬在纳摩尔浓度下就能阻断类胡萝卜素色素的生物合成。这种作用是通过竞争性抑制金黄色葡萄球菌的脱叶菌烯脱饱和酶（CrtN）介导的，CrtN 是类胡萝卜素色素合成的必需酶。我们发现，萘替芬在小鼠感染模型中减弱了各种临床分离的金黄色葡萄球菌，包括耐甲氧西林金黄色葡萄球菌（MRSA）菌株的毒力。具体来说，我们确定萘替芬是一种有效的 CrtN 抑制剂先导化合物。总之，这些发现表明，萘替芬可以作为一种化学探针来操纵 CrtN 的活性，为 CrtN 是治疗金黄色葡萄球菌感染的可成药靶点提供了概念验证。
