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

44 Scopus citations

Abstract

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
JournalChemBioChem
Volume14
Issue number16
DOIs
StatePublished - Nov 2013

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Chemical and structural insights into the regioversatility of the aminoglycoside acetyltransferase eis'. Together they form a unique fingerprint.

Cite this