Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB

被引：109

作者：

Chen, Wenjing ^{[1
,2
]}

Biswas, Tapan ^{[3
]}

Porter, Vanessa R. ^{[2
,3
]}

Tsodikov, Oleg V. ^{[1
,3
]}

Garneau-Tsodikova, Sylvie ^{[1
,2
,3
]}

机构：

[1] Univ Michigan, Chem Biol Doctoral Program, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA

[3] Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 24期

关键词：

bacterial resistance; product-bound complex; ribosome inhibitor; catalytic efficiency; crystal structure; STEROL CARRIER PROTEIN-2; MYCOBACTERIUM-TUBERCULOSIS; AMINOGLYCOSIDE 2'-N-ACETYLTRANSFERASE; ANTIBIOTIC-RESISTANCE; SERRATIA-MARCESCENS; GENE; SURVIVAL; OVEREXPRESSION; MACROPHAGES; EXPRESSION;

D O I：

10.1073/pnas.1105379108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 substratebinding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.

引用

页码：9804 / 9808

页数：5

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