Willby Melisa J, Green Keith D, Gajadeera Chathurada S, Hou Caixia, Tsodikov Oleg V, Posey James E, Garneau-Tsodikova Sylvie
Division of Tuberculosis Elimination, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention , Atlanta, Georgia 30329, United States.
Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky 40536-0596, United States.
ACS Chem Biol. 2016 Jun 17;11(6):1639-46. doi: 10.1021/acschembio.6b00110. Epub 2016 Apr 7.
A major cause of tuberculosis (TB) resistance to the aminoglycoside kanamycin (KAN) is the Mycobacterium tuberculosis (Mtb) acetyltransferase Eis. Upregulation of this enzyme is responsible for inactivation of KAN through acetylation of its amino groups. A 123 000-compound high-throughput screen (HTS) yielded several small-molecule Eis inhibitors that share an isothiazole S,S-dioxide heterocyclic core. These were investigated for their structure-activity relationships. Crystal structures of Eis in complex with two potent inhibitors show that these molecules are bound in the conformationally adaptable aminoglycoside binding site of the enzyme, thereby obstructing binding of KAN for acetylation. Importantly, we demonstrate that several Eis inhibitors, when used in combination with KAN against resistant Mtb, efficiently overcome KAN resistance. This approach paves the way toward development of novel combination therapies against aminoglycoside-resistant TB.
结核分枝杆菌（Mtb）对氨基糖苷类卡那霉素（KAN）产生耐药性的一个主要原因是结核分枝杆菌乙酰转移酶Eis。该酶的上调通过使KAN的氨基乙酰化而导致其失活。一项包含123000种化合物的高通量筛选（HTS）产生了几种具有异噻唑S,S - 二氧化物杂环核心的小分子Eis抑制剂。对这些抑制剂进行了构效关系研究。Eis与两种强效抑制剂复合物的晶体结构表明，这些分子结合在该酶构象可适应的氨基糖苷类结合位点中，从而阻碍KAN结合进行乙酰化。重要的是，我们证明了几种Eis抑制剂与KAN联合用于对抗耐药性Mtb时，能有效克服KAN耐药性。这种方法为开发针对氨基糖苷类耐药结核病的新型联合疗法铺平了道路。
