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

Producción científica: Article › revisión exhaustiva

62 Citas (Scopus)

Resumen

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

Idioma original	English
Número de artículo	dks497
Páginas (desde-hasta)	800-805
Número de páginas	6
Publicación	Journal of Antimicrobial Chemotherapy
Volumen	68
N.º	4
DOI	https://doi.org/10.1093/jac/dks497
Estado	Published - abr 2013

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)
National Institute of Allergy and Infectious Diseases	R01AI090048
American Foundation for Pharmaceutical Education
University of Michigan Hospital

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

Pharmacology
Microbiology (medical)
Pharmacology (medical)
Infectious Diseases

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10.1093/jac/dks497

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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.

AU - Pricer, Rachel E.

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

KW - Anti-tuberculosis drugs

KW - Antibiotic resistance

KW - Mechanisms of resistance

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Unexpected N-acetylation of capreomycin by mycobacterial Eis enzymes

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

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