Aminoglycoside multiacetylating activity of the enhanced intracellular survival protein from Mycobacterium smegmatis and its inhibition

Wenjing Chen, Keith D. Green, Oleg V. Tsodikov, Sylvie Garneau-Tsodikova

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


The enhanced intracellular survival (Eis) protein improves the survival of Mycobacterium smegmatis (Msm) in macrophages and functions as the acetyltransferase responsible for kanamycin A resistance, a hallmark of extensively drug-resistant (XDR) tuberculosis, in a large number of Mycobacterium tuberculosis (Mtb) clinical isolates. We recently demonstrated that Eis from Mtb (Eis-Mtb) efficiently multiacetylates a variety of aminoglycoside (AG) antibiotics. Here, to gain insight into the origin of substrate selectivity of AG multiacetylation by Eis, we analyzed AG acetylation by Eis-Msm, investigated its inhibition, and compared these functions to those of Eis-Mtb. Even though for several AGs the multiacetylation properties of Eis-Msm and Eis-Mtb are similar, there are three major differences. (i) Eis-Msm diacetylates apramycin, a conformationally constrained AG, which Eis-Mtb cannot modify. (ii) Eis-Msm triacetylates paromomycin, which can be only diacetylated by Eis-Mtb. (iii) Eis-Msm only monoacetylates hygromycin, a structurally unique AG that is diacetylated by Eis-Mtb. Several nonconserved amino acid residues lining the AG-binding pocket of Eis are likely responsible for these differences between the two Eis homologues. Specifically, we propose that because the AG-binding pocket of Eis-Msm is more open than that of Eis-Mtb, it accommodates apramycin for acetylation in Eis-Msm, but not in Eis-Mtb. We also demonstrate that inhibitors of Eis-Mtb that we recently discovered can inhibit Eis-Msm activity. These observations help define the structural origins of substrate preference among Eis homologues and suggest that Eis-Mtb inhibitors may be applied against all pathogenic mycobacteria to overcome AG resistance caused by Eis upregulation (Chemical Equation Presented).

Original languageEnglish
Pages (from-to)4959-4967
Number of pages9
Issue number24
StatePublished - Jun 19 2012

ASJC Scopus subject areas

  • Biochemistry


Dive into the research topics of 'Aminoglycoside multiacetylating activity of the enhanced intracellular survival protein from Mycobacterium smegmatis and its inhibition'. Together they form a unique fingerprint.

Cite this