PDF(Pubmed)
Abstract：
Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.
摘要：
抗微生物耐药性（AMR）是对全球健康的最大威胁之一。只要采取传统的抗生素方法，AMR的出现和药物开发之间的持续斗争将极难停止。为了克服这种僵局,我们在这里关注III型分泌系统（T3SS），在许多革兰氏阴性致病菌中高度保守。已知T3SS在建立疾病过程中是不可缺少的,但不是病原体存活所必需的。因此,T3SS抑制剂可能是创新的抗感染剂，可以显着降低对治疗耐药菌株的进化选择压力。基于这个概念,我们之前确定了一种聚酮天然产品，aurodox(AD)，作为使用我们原始筛选系统的特异性T3SS抑制剂。然而,尽管它有望成为AD的独特抗感染药物，AD的分子靶标仍不清楚。在本文中,使用基于化学和遗传生物学的创新方法，我们显示AD与腺苷琥珀酸合酶（PurA）结合，抑制T3SS分泌蛋白的产生，在体外和体内实验中导致细菌毒力的表达。我们的发现阐明了PurA作为抗感染药物和疫苗接种靶标的潜力，并可能为PurA在T3SS调节中的应用开辟了一条途径。
