Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes

Jacob L. Houghton; Keith D. Green; Rachel E. Pricer; Abdelrahman S. Mayhoub; Sylvie Garneau-Tsodikova

doi:10.1093/jac/dks497

Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes

Jacob L. Houghton, Keith D. Green, Rachel E. Pricer, Abdelrahman S. Mayhoub, Sylvie Garneau-Tsodikova

Research output: Contribution to journal › Article › peer-review

59 Scopus citations

Abstract

Objectives: The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis_Mtb), a regioversatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis_Mtb and of its homologue from Mycobacterium smegmatis (Eis_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds. Methods and results: Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its b-lysine side chain. Using Eis_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the 1-amine of the b-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Conclusions: Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds

Original language	English
Article number	dks497
Pages (from-to)	800-805
Number of pages	6
Journal	Journal of Antimicrobial Chemotherapy
Volume	68
Issue number	4
DOIs	https://doi.org/10.1093/jac/dks497
State	Published - Apr 2013

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health (NIH) grant AI090048 (S. G.-T.). J. H. L. was supported by the Cellular Biotechnology Training Program (CBTP) and an American Foundation of Pharmaceutical Education (AFPE) Fellowship. R. E. P. and J. H. L were supported by Rackham Merit Fellowships at the University of Michigan. R. E. P. was supported by the Chemistry Biology Interface (CBI) Training Program at the University of Michigan.

Funding

This work was supported by the National Institutes of Health (NIH) grant AI090048 (S. G.-T.). J. H. L. was supported by the Cellular Biotechnology Training Program (CBTP) and an American Foundation of Pharmaceutical Education (AFPE) Fellowship. R. E. P. and J. H. L were supported by Rackham Merit Fellowships at the University of Michigan. R. E. P. was supported by the Chemistry Biology Interface (CBI) Training Program at the University of Michigan.

Funders	Funder number
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases	R01AI090048
American Foundation for Pharmaceutical Education
University of Michigan Hospital

Keywords

Anti-tuberculosis drugs
Antibiotic resistance
Mechanisms of resistance

ASJC Scopus subject areas

Pharmacology
Microbiology (medical)
Pharmacology (medical)
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jac/dks497

Cite this

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title = "Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes",

abstract = "Objectives: The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis\_Mtb), a regioversatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis\_Mtb and of its homologue from Mycobacterium smegmatis (Eis\_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds. Methods and results: Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its b-lysine side chain. Using Eis\_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the 1-amine of the b-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Conclusions: Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds",

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note = "Funding Information: This work was supported by the National Institutes of Health (NIH) grant AI090048 (S. G.-T.). J. H. L. was supported by the Cellular Biotechnology Training Program (CBTP) and an American Foundation of Pharmaceutical Education (AFPE) Fellowship. R. E. P. and J. H. L were supported by Rackham Merit Fellowships at the University of Michigan. R. E. P. was supported by the Chemistry Biology Interface (CBI) Training Program at the University of Michigan.",

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AU - Green, Keith D.

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AU - Mayhoub, Abdelrahman S.

AU - Garneau-Tsodikova, Sylvie

N1 - Funding Information: This work was supported by the National Institutes of Health (NIH) grant AI090048 (S. G.-T.). J. H. L. was supported by the Cellular Biotechnology Training Program (CBTP) and an American Foundation of Pharmaceutical Education (AFPE) Fellowship. R. E. P. and J. H. L were supported by Rackham Merit Fellowships at the University of Michigan. R. E. P. was supported by the Chemistry Biology Interface (CBI) Training Program at the University of Michigan.

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N2 - Objectives: The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis_Mtb), a regioversatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis_Mtb and of its homologue from Mycobacterium smegmatis (Eis_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds. Methods and results: Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its b-lysine side chain. Using Eis_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the 1-amine of the b-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Conclusions: Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds

AB - Objectives: The enhanced intracellular survival (Eis) protein from Mycobacterium tuberculosis (Eis_Mtb), a regioversatile N-acetyltransferase active towards many aminoglycosides (AGs), confers resistance to kanamycin A in some cases of extensively drug-resistant tuberculosis (XDR-TB). We assessed the activity of Eis_Mtb and of its homologue from Mycobacterium smegmatis (Eis_Msm) against a panel of anti-tuberculosis (TB) drugs and lysine-containing compounds. Methods and results: Both enzymes acetylated capreomycin and some lysine-containing compounds, but not other non-AG non-lysine-containing drugs tested. Modelling studies predicted the site of modification on capreomycin to be one of the two primary amines in its b-lysine side chain. Using Eis_Mtb, we established via nuclear magnetic resonance (NMR) spectroscopy that acetylation of capreomycin occurs on the 1-amine of the b-lysine side chain. Using Msm, we also demonstrated for the first time to our knowledge that acetylation of capreomycin results in deactivation of the drug. Conclusions: Eis is a unique acetyltransferase capable of inactivating the anti-TB drug capreomycin, AGs and other lysine-containing compounds

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Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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