Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB

Journal Article · Tue Sep 06 04:00:00 EDT 2011 · Proc. Natl. Acad. Sci. USA

DOI:https://doi.org/10.1073/pnas.1105379108· OSTI ID:1018861

Chen, Wenjing; Biswas, Tapan; Porter, Vanessa R; Tsodikov, Oleg V; Garneau-Tsodikova, Sylvie ^[1]

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1. Michigan

The emergence of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis (TB) is a serious global threat. Aminoglycoside antibiotics are used as a last resort to treat XDR-TB. Resistance to the aminoglycoside kanamycin is a hallmark of XDR-TB. Here, we reveal the function and structure of the mycobacterial protein Eis responsible for resistance to kanamycin in a significant fraction of kanamycin-resistant Mycobacterium tuberculosis clinical isolates. We demonstrate that Eis has an unprecedented ability to acetylate multiple amines of many aminoglycosides. Structural and mutagenesis studies of Eis indicate that its acetylation mechanism is enabled by a complex tripartite fold that includes two general control non-derepressible 5 (GCN5)-related N-acetyltransferase regions. An intricate negatively charged substrate-binding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: UNIVERSITY
• OSTI ID: 1018861
• Journal Information: Proc. Natl. Acad. Sci. USA, Journal Name: Proc. Natl. Acad. Sci. USA Journal Issue: (24) ; 06, 2011 Vol. 108; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
ACETYLATION
AMINES
ANTIBIOTICS
MUTAGENESIS
MYCOBACTERIUM TUBERCULOSIS
PROTEINS
TARGETS
TUBERCULOSIS