Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9804-8. doi: 10.1073/pnas.1105379108. Epub 2011 May 31.
The emergence of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis (TB) is a serious global threat. Aminoglycoside antibiotics are used as a last resort to treat XDR-TB. Resistance to the aminoglycoside kanamycin is a hallmark of XDR-TB. Here, we reveal the function and structure of the mycobacterial protein Eis responsible for resistance to kanamycin in a significant fraction of kanamycin-resistant Mycobacterium tuberculosis clinical isolates. We demonstrate that Eis has an unprecedented ability to acetylate multiple amines of many aminoglycosides. Structural and mutagenesis studies of Eis indicate that its acetylation mechanism is enabled by a complex tripartite fold that includes two general control non-derepressible 5 (GCN5)-related N-acetyltransferase regions. An intricate negatively charged substrate-binding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.
耐多药和广泛耐药（XDR）结核病（TB）的出现是一个严重的全球威胁。氨基糖苷类抗生素被用作治疗 XDR-TB 的最后手段。对氨基糖苷类药物卡那霉素的耐药性是 XDR-TB 的一个标志。在这里，我们揭示了分枝杆菌蛋白 Eis 的功能和结构，该蛋白负责对抗生素卡那霉素耐药的结核分枝杆菌临床分离株的一部分具有耐药性。我们证明，Eis 具有前所未有的乙酰化多种氨基糖苷类药物多种胺的能力。Eis 的结构和突变研究表明，其乙酰化机制是由一个复杂的三部分折叠所实现的，其中包括两个一般控制非去阻遏 5（GCN5）相关的 N-乙酰转移酶区域。Eis 的复杂带负电荷的底物结合口袋是潜在的新抗结核药物的靶点，有望克服氨基糖苷类药物的耐药性。
