State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, 200237, China.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, China.
Nat Commun. 2019 Jan 16;10(1):258. doi: 10.1038/s41467-018-08241-3.
Antimicrobial resistance is a public health emergency and warrants coordinated global efforts. Challenge is that no alternative molecular platform has been identified for discovery of abundant antimicrobial hit compounds. Xanthene libraries have been screened for bioactive compounds. However, the potentially accessible chemistry space of xanthene dyes is limited by the existing xanthene synthesis. Herein we report a mild one-step synthesis, which permits late-stage introduction of a xanthene moiety onto i.e. natural products, pharmaceuticals, and bioactive compounds and construction of a focused library of rhodamine dyes exhibiting facile functional, topographical and stereochemical diversity. In vitro screening yields 37 analogs with mid-to-high bactericidal activity against WHO priority drug-resistant pathogens. These findings suggest that synthetic dye libraries exhibiting high structural diversity is a feasible chemical space combating antibacterial resistance, to complement the natural sources.
抗微生物药物耐药性是一个公共卫生紧急事件，需要协调全球努力。挑战在于，尚未确定用于发现大量抗菌命中化合物的替代分子平台。已经对呫吨文库进行了生物活性化合物的筛选。然而，呫吨染料的潜在可及化学空间受到现有呫吨合成的限制。在此，我们报告了一种温和的一步合成方法，该方法允许在天然产物、药物和生物活性化合物上后期引入呫吨部分，并构建了一个具有丰富结构多样性的聚焦罗丹明染料文库，展示了易于实现的功能、形貌和立体化学多样性。体外筛选得到 37 个具有中等到高杀菌活性的类似物，可对抗世卫组织优先抗药性病原体。这些发现表明，展示高结构多样性的合成染料文库是对抗细菌耐药性的可行化学空间，可以补充天然来源。
