TY - JOUR
T1 - Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB
AU - Chen, Wenjing
AU - Biswas, Tapan
AU - Porter, Vanessa R.
AU - Tsodikov, Oleg V.
AU - Garneau-Tsodikova, Sylvie
PY - 2011/6/14
Y1 - 2011/6/14
N2 - 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 substratebinding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.
AB - 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 substratebinding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.
KW - Bacterial resistance
KW - Catalytic efficiency
KW - Crystal structure
KW - Product-bound complex
KW - Ribosome inhibitor
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U2 - 10.1073/pnas.1105379108
DO - 10.1073/pnas.1105379108
M3 - Article
C2 - 21628583
AN - SCOPUS:79959931142
SN - 0027-8424
VL - 108
SP - 9804
EP - 9808
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -
