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

Wenjing Chen, Tapan Biswas, Vanessa R. Porter, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)9804-9808
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number24
DOIs
StatePublished - Jun 14 2011

Keywords

  • Bacterial resistance
  • Catalytic efficiency
  • Crystal structure
  • Product-bound complex
  • Ribosome inhibitor

ASJC Scopus subject areas

  • General

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