Environmental DNA-encoded antibiotics fasamycins A and B inhibit FabF in type II fatty acid biosynthesis.
Environmental DNA-encoded antibiotics fasamycins A and B inhibit FabF in type II fatty acid biosynthesis.
复制标题
DOI：
10.1021/ja207662w
复制
发表时间：
2012-02-15
影响因子：
15
通讯作者：
Brady, Sean F.
中科院分区：
文献类型：
--
作者：
Feng, Zhiyang;Chakraborty, Debjani;Dewell, Scott B.;Reddy, Boojala Vijay B.;Brady, Sean F.
在最近的一项直接从土壤中克隆的聚酮生物合成基因簇的研究中，我们分离出了两种抗生素法那霉素A和B，它们对耐甲氧西林金黄色葡萄球菌和耐万古霉素粪肠球菌表现出活性。为了鉴定法沙霉素的靶点，从大肠杆菌的野生型培养物中选择具有升高的法沙霉素A MIC的突变体。faecalis OG1RF.这些突变体的下一代测序，结合体外生物化学测定，表明法霉素抑制FabF的II型脂肪酸生物合成（FASII）。候选基因过表达研究还表明，法沙霉素抗性是由fabF过表达赋予的。基于与已知的FASII抑制剂的比较和计算机对接研究，预测法霉素中所见的氯-偕-二甲基-蒽酮亚结构代表天然存在的FabF特异性抗生素药效团。该药效团的优化应该产生具有更高效力和不同活性谱的FabF特异性抗生素。这项研究表明，不依赖于培养的抗生素发现方法有可能提供与目前临床使用的抗生素不同的作用模式的新型代谢物。
In a recent study of polyketide biosynthetic gene clusters cloned directly from soil, we isolated two antibiotics, fasamycin A and B, which showed activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Entero-coccus faecalis. To identify the target of the fasamycins, mutants with elevated fasamycin A MICs 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. Based on 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 spectrums 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 antibiotics currently in clinical use.
登录
查看更多内容
影响因子：
12.3
作者：
Bourgogne, Agathe;Garsin, Danielle A.;Qin, Xiang;Singh, Kavindra V.;Sillanpaa, Jouko;Yerrapragada, Shailaja;Ding, Yan;Dugan-Rocha, Shannon;Buhay, Christian;Shen, Hua;Chen, Guan;Williams, Gabrielle;Muzny, Donna;Maadani, Arash;Fox, Kristina A.;Gioia, Jason;Chen, Lei;Shang, Yue;Arias, Cesar A.;Nallapareddy, Sreedhar R.;Zhao, Meng;Prakash, Vittal P.;Chowdhury, Shahreen;Jiang, Huaiyang;Gibbs, Richard A.;Murray, Barbara E.;Highlander, Sarah K.;Weinstock, George M.
通讯作者：
Weinstock, George M.
影响因子：
11.8
作者：
Klein E;Smith DL;Laxminarayan R
通讯作者：
Laxminarayan R
影响因子：
82.9
作者：
Vilcheze, Catherine;Wang, Feng;Jacobs, William R., Jr.
通讯作者：
Jacobs, William R., Jr.
影响因子：
7
作者：
Lunter, Gerton;Goodson, Martin
通讯作者：
Goodson, Martin
影响因子：
64.8
作者：
Wang, J;Soisson, SM;Singh, SB
通讯作者：
Singh, SB