近日,，科學(xué)家報(bào)道了他們運(yùn)用一種新的技術(shù)發(fā)現(xiàn)餓了兩種潛在的抗生素,，新抗生素可以有效治療耐甲氧西林金黃色葡萄球菌MRSA的感染,，相關(guān)研究成果刊登在了最新一期的國(guó)際著名化學(xué)雜志The Journal of the American Chemical Society(JACS)上,。
研究者Sean Brady和同事表示,，當(dāng)前急需一種新的抗菌藥物來應(yīng)對(duì)不斷改變抗性的病原菌，比如，耐甲氧西林金黃色葡萄球菌（MRSA）,，基本上對(duì)大部分已知的抗生素均有抗性,，在美國(guó)每年都會(huì)有280000人會(huì)被MRSA感染，近乎20000人因MRSA感染而死,。我們開發(fā)抗生素的途徑已經(jīng)延伸到了識(shí)別和培養(yǎng)新的細(xì)菌來對(duì)抗別的細(xì)菌的感染,。環(huán)境埋藏物是最大的新抗生素的潛在來源，研究者然后分析了細(xì)菌的組分,，看是否可以制造某種像抗生素的物質(zhì)來殺死其他微生物,，但是大部分在自然界發(fā)現(xiàn)的微生物并不能夠在實(shí)驗(yàn)室培養(yǎng)，這就是為什么Brady和他同事為什么找到一種新的方法來解決此問題的原因,。
研究者從不能夠在實(shí)驗(yàn)室培養(yǎng)的土壤細(xì)菌中移去了它們的DNA,，然后他們把DNA轉(zhuǎn)入能夠在實(shí)驗(yàn)室培養(yǎng)的細(xì)菌中，這些細(xì)菌就成為宿主,，產(chǎn)生原始菌的新的DNA,，這種方法就可以讓研究者對(duì)土壤細(xì)菌產(chǎn)生的物質(zhì)進(jìn)行深入研究，運(yùn)用宏基因組學(xué)的方法,，識(shí)別出了兩種可以殺死MRSA和耐萬古霉素糞腸球菌的可能的新型抗生素,，命名為fasamycin A和fasamycin B，研究者同時(shí)揭示了這兩種新型抗生素的作用機(jī)理,，最后研究者表示,，宏基因組學(xué)的方法可以幫助我們獲得自然界中不易獲得的新型天然抗生素。
研究者的研究基金來自于國(guó)立健康學(xué)院和霍華德休斯醫(yī)學(xué)院,。（生物谷：T.Shen編譯）
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.
