期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 108, 期 24, 页码 9804-9808出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1105379108
关键词
bacterial resistance; product-bound complex; ribosome inhibitor; catalytic efficiency; crystal structure
资金
- Life Sciences Institute
- College of Pharmacy at the University of Michigan
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.
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