近日，科学家报道了他们运用一种新的技术发现饿了两种潜在的抗生素，新抗生素可以有效治疗耐甲氧西林金黄色葡萄球菌MRSA的感染，相关研究成果刊登在了最新一期的国际著名化学杂志The Journal of the American Chemical Society(JACS)上。
研究者Sean Brady和同事表示，当前急需一种新的抗菌药物来应对不断改变抗性的病原菌，比如，耐甲氧西林金黄色葡萄球菌（MRSA），基本上对大部分已知的抗生素均有抗性，在美国每年都会有280000人会被MRSA感染，近乎20000人因MRSA感染而死。我们开发抗生素的途径已经延伸到了识别和培养新的细菌来对抗别的细菌的感染。环境埋藏物是最大的新抗生素的潜在来源，研究者然后分析了细菌的组分，看是否可以制造某种像抗生素的物质来杀死其他微生物，但是大部分在自然界发现的微生物并不能够在实验室培养，这就是为什么Brady和他同事为什么找到一种新的方法来解决此问题的原因。
研究者从不能够在实验室培养的土壤细菌中移去了它们的DNA，然后他们把DNA转入能够在实验室培养的细菌中，这些细菌就成为宿主，产生原始菌的新的DNA，这种方法就可以让研究者对土壤细菌产生的物质进行深入研究，运用宏基因组学的方法，识别出了两种可以杀死MRSA和耐万古霉素粪肠球菌的可能的新型抗生素，命名为fasamycin A和fasamycin B，研究者同时揭示了这两种新型抗生素的作用机理，最后研究者表示，宏基因组学的方法可以帮助我们获得自然界中不易获得的新型天然抗生素。
研究者的研究基金来自于国立健康学院和霍华德休斯医学院。（生物谷：T.Shen编译）
doi:10.1021/ja207662w
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Environmental DNA-Encoded Antibiotics Fasamycins A and B Inhibit FabF in Type II Fatty Acid Biosynthesis
Zhiyang Feng†, Debjani Chakraborty†, Scott B. Dewell‡, Boojala Vijay B. Reddy†§, and Sean F. Brady*†§
In a recent study of polyketide biosynthetic gene clusters cloned directly from soil, we isolated two antibiotics, fasamycins A and B, which showed activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. To identify the target of the fasamycins, mutants with elevated fasamycin A minimum inhibitory concentrations were selected from a wild-type culture of E. faecalis OG1RF. Next-generation sequencing of these mutants, in conjunction with in vitro biochemical assays, showed that the fasamycins inhibit FabF of type II fatty acid biosynthesis (FASII). Candidate gene overexpression studies also showed that fasamycin resistance is conferred by fabF overexpression. On the basis of comparisons with known FASII inhibitors and in silico docking studies, the chloro-gem-dimethyl-anthracenone substructure seen in the fasamycins is predicted to represent a naturally occurring FabF-specific antibiotic pharmacophore. Optimization of this pharmacophore should yield FabF-specific antibiotics with increased potencies and differing spectra of activity. This study demonstrates that culture-independent antibiotic discovery methods have the potential to provide access to novel metabolites with modes of action that differ from those of antibiotics currently in clinical use.
