Nature子刊:从土壤中取利福平同源物,杀耐利福平细菌

创作:gaoch 审核:gaoch 10月11日
利用简并引物从约1500个土壤样本DNA中扩增利福平生物合成基因簇(BGC),发现大约一半的土壤中含有类利福平的BGC;
通过黏粒文库筛选最终得到3个利福平类似物,确定其分子结构后命名为康乐霉素(kanglemycin);
康乐霉素也能与RNA聚合酶结合,具有与利福平相同的核心作用位点;
不过,一些康乐霉素特有的基团还能与RNA聚合酶建立新的联系,产生了新的作用位点;
新的作用位点通过干扰5'起始底物结合的方式对利福平耐药菌发挥作用。
延伸阅读
Nature Communications [IF:12.353]

Rifamycin congeners kanglemycins are active against rifampicin-resistant bacteria via a distinct mechanism

利福平同源物康乐霉素通过不同的机制对抗利福平细菌产生活性

10-08, Article, 10.1038/s41467-018-06587-2more

Abstract:
Rifamycin antibiotics (Rifs) target bacterial RNA polymerases (RNAPs) and are widely used to treat infections including tuberculosis. The utility of these compounds is threatened by the increasing incidence of resistance (RifR). As resistance mechanisms found in clinical settings may also occur in natural environments, here we postulated that bacteria could have evolved to produce rifamycin congeners active against clinically relevant resistance phenotypes. We survey soil metagenomes and identify a tailoring enzyme-rich family of gene clusters encoding biosynthesis of rifamycin congeners (kanglemycins, Kangs) with potent in vivo and in vitro activity against the most common clinically relevant RifR mutations. Our structural and mechanistic analyses reveal the basis for Kang inhibition of RifR RNAP. Unlike Rifs, Kangs function through a mechanism that includes interfering with 5′-initiating substrate binding. Our results suggest that examining soil microbiomes for new analogues of clinically used antibiotics may uncover metabolites capable of circumventing clinically important resistance mechanisms.

First Authors:
James Peek,Mirjana Lilic

Correspondence Authors:
Elizabeth A Campbell,Sean F Brady

All Authors:
James Peek,Mirjana Lilic,Daniel Montiel,Aleksandr Milshteyn,Ian Woodworth,John B Biggins,Melinda A Ternei,Paula Y Calle,Michael Danziger,Thulasi Warrier,Kohta Saito,Nathaniel Braffman,Allison Fay,Michael S Glickman,Seth A Darst,Elizabeth A Campbell,Sean F Brady