华中科技大学Sci Rep发现对抗超级耐药细菌的天然抗生素

“老药新用”的药物开发策略使一些淘汰的“老药”重现生机。最经典的例子当然是辉瑞的心血管“淘汰药物选手”--万艾可（伟哥），改变适应症使其成为年销售过5亿的非处方药。2015年6月，一个50年前发现的真菌代谢产物 aspergillomarasmine A 登上了 Nature杂志，因为在高通量筛选中发现了它对 metallo-β-lactamase的作用，研究人员就此进行开发，发现其具有协同抗产酶耐药菌的活性，而目前产酶耐药菌正是临床治疗的重难点。

来自华中科技大学同济药学院的张勇慧教授和李华教授课题组受其启发，在高通量抗耐药菌活性筛选中发现“老药”——已知的天然产物 Fonsecinones ，对临床4 种常见耐药菌（ESBL-producing E. coli, p. aeruginosa，E. faecalis，MRSA）具有较好抗菌活性。

为了进一步明确其抗菌靶点，进行后续的科研开发，他们采用计算机模拟“广泛对接”，文献调研“精细对接”的方式寻找可能的靶点。最终将其抗菌靶点锁定为细菌脂肪酸代谢酶系的关键限速酶FabI，并运用最新的微量热泳(MST)生物分子分析技术，酶抑制活性测试，证实了此靶点的正确性。

MRSA，即耐甲氧西林金葡菌，是具有广谱耐药性的超级细菌，为医院及社区感染的主要病原菌之一，它对β-内酰胺类和头孢类抗生素均耐药，对氨基糖苷类、大环内酯类、四环素类、氟喹喏酮类、磺胺类、利福平均产生不同程度的耐药，只对万古霉素敏感。而最近有报道甚至出现抗万古霉素的抗药菌，在这种情况下，人类急需新的抗生素构建对细菌的最后防线。这项研究运用最新的基于结构的药物发现技术，重新发现了“老药”天然Fonsecinones的作用机制，使之成为具有潜力的抗耐药菌候选药物和先导化合物。

这一研究成果公布在Scientific Reports杂志（最新影响因子5.578）上，文章的第一作者是博士研究生何艳（完成了实验的主要部分）。

原文摘要：

Fungal naphtho-γ-pyrones: potent antibiotics for drug-resistant microbial pathogens

Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, p. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1–8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1–8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens.