Chemical and structural insights into the regioversatility of the aminoglycoside acetyltransferase eis

Jacob L. Houghton, Tapan Biswas, Wenjing Chen, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


A recently discovered cause of tuberculosis resistance to a drug of last resort, the aminoglycoside kanamycin, results from modification of this drug by the enhanced intracellular survival (Eis) protein. Eis is a structurally and functionally unique acetyltransferase with an unusual capability of acetylating aminoglycosides at multiple positions. The extent of this regioversatility and its defining protein features are unclear. Herein, we determined the positions and order of acetylation of five aminoglycosides by NMR spectroscopy. This analysis revealed unprecedented acetylation of the 3′′-amine of kanamycin, amikacin, and tobramycin, and the γ-amine of the 4-amino-2-hydroxybutyryl group of amikacin. A crystal structure of Eis in complex with coenzyme A and tobramycin revealed how tobramycin can be accommodated in the Eis active site in two binding modes, consistent with its diacetylation. These studies, describing chemical and structural details of acetylation, will guide future efforts towards designing aminoglycosides and Eis inhibitors to overcome resistance in tuberculosis.

Original languageEnglish
Pages (from-to)2127-2135
Number of pages9
Issue number16
StatePublished - Nov 2013


  • Bacterial resistance
  • Enhanced intracellular survival protein
  • Enzymatic reaction
  • Multi-acetylation
  • Tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry


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