Department of Microbiology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
Research Centre of Infection and Immunology, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.
mBio. 2017 Sep 5;8(5):e01224-17. doi: 10.1128/mBio.01224-17.
, especially methicillin-resistant (MRSA), is a life-threatening pathogen in hospital- and community-acquired infections. The golden-colored carotenoid pigment of , staphyloxanthin, contributes to the resistance to reactive oxygen species (ROS) and host neutrophil-based killing. Here, we describe a novel inhibitor (NP16) of pigment production that reduces the survival of under oxidative stress conditions. Carotenoid components analysis, enzyme inhibition, and mutational studies indicated that the molecular target of NP16 is dehydrosqualene desaturase (CrtN). treated with NP16 showed increased susceptibility to human neutrophil killing and to innate immune clearance in a mouse infection model. Our study validates CrtN as a novel druggable target in and presents a potent and effective lead compound for the development of virulence factor-based therapy against staphyloxanthin contributes substantially to pathogenesis by interfering with host immune clearance mechanisms, but it has little impact on survival of the bacterium. Agents blocking staphyloxanthin production may discourage the establishment and maintenance of bacterial infection without exerting selective pressure for antimicrobial resistance. Our newly discovered CrtN inhibitor, NP16, may offer an effective strategy for combating infections.
金黄色葡萄球菌（Staphylococcus aureus），尤其是耐甲氧西林金黄色葡萄球菌（MRSA），是医院内和社区获得性感染中一种危及生命的病原体。金黄色葡萄球菌的金黄色类胡萝卜素色素——粪卟啉，有助于其抵抗活性氧（ROS）和宿主中性粒细胞介导的杀伤。在这里，我们描述了一种新型抑制剂（NP16），它可以抑制色素的产生，降低金黄色葡萄球菌在氧化应激条件下的存活率。类胡萝卜素成分分析、酶抑制和突变研究表明，NP16 的分子靶标是脱水鲨烯环化酶（CrtN）。用 NP16 处理的金黄色葡萄球菌在氧化应激条件下对人类中性粒细胞杀伤和先天免疫清除的敏感性增加。我们的研究验证了 CrtN 是金黄色葡萄球菌中一个新的可成药靶标，并为基于毒力因子的金黄色葡萄球菌治疗方法的开发提供了一种有效且有效的先导化合物，以对抗金黄色葡萄球菌。粪卟啉在很大程度上通过干扰宿主免疫清除机制而促进发病机制，但对细菌的生存影响不大。抑制粪卟啉产生的药物可能会阻止细菌感染的建立和维持，而不会对抗菌药物耐药性产生选择性压力。我们新发现的 CrtN 抑制剂 NP16 可能为对抗金黄色葡萄球菌感染提供了一种有效的策略。
