Chemical and Structural Insights into the Regioversatility of the Aminoglycoside Acetyltransferase Eis

Authors

  • Dr. Jacob L. Houghton,

    1. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA)
    2. Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 (USA)
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    • These two authors contributed equally to this work.

  • Dr. Tapan Biswas,

    1. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109 (USA)
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    • These two authors contributed equally to this work.

  • Dr. Wenjing Chen,

    1. Chemical Biology Doctoral Program, University of Michigan, Ann Arbor, MI 48109 (USA)
    2. Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109 (USA)
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  • Dr. Oleg V. Tsodikov,

    Corresponding author
    1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596 (USA)
    • Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596 (USA)

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  • Dr. Sylvie Garneau-Tsodikova

    Corresponding author
    1. Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596 (USA)
    • Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, 40536-0596 (USA)

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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.

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