{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:28:54Z","timestamp":1790810934424,"version":"4.1.0"},"reference-count":29,"publisher":"National Academy of Sciences","issue":"24","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,6,14]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    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                    <jats:italic>N<\/jats:italic>\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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1105379108","type":"journal-article","created":{"date-parts":[[2011,5,31]],"date-time":"2011-05-31T22:20:55Z","timestamp":1306880455000},"page":"9804-9808","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":117,"title":["Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB"],"prefix":"10.1073","volume":"108","author":[{"given":"Wenjing","family":"Chen","sequence":"first","affiliation":[{"name":"Life Sciences Institute;"},{"name":"Chemical Biology Doctoral Program; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapan","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa R.","family":"Porter","sequence":"additional","affiliation":[{"name":"Life Sciences Institute;"},{"name":"Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oleg V.","family":"Tsodikov","sequence":"additional","affiliation":[{"name":"Chemical Biology Doctoral Program; and"},{"name":"Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvie","family":"Garneau-Tsodikova","sequence":"additional","affiliation":[{"name":"Life Sciences Institute;"},{"name":"Chemical Biology Doctoral Program; and"},{"name":"Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,5,31]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/S1473-3099(10)70139-0","article-title":"Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis","volume":"10","author":"Caminero JA","year":"2010","unstructured":"JA Caminero, G Sotgiu, A Zumla, GB Migliori, Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis. Lancet Infect Dis 10, 621\u2013629 (2010).","journal-title":"Lancet Infect Dis"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1002\/cbic.200900779","article-title":"The future of aminoglycosides: The end or renaissance?","volume":"11","author":"Houghton JL","year":"2010","unstructured":"JL Houghton, KD Green, W Chen, S Garneau-Tsodikova, The future of aminoglycosides: The end or renaissance? ChemBioChem 11, 880\u2013902 (2010).","journal-title":"ChemBioChem"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/35030019","article-title":"Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics","volume":"407","author":"Carter AP","year":"2000","unstructured":"AP Carter, et al., Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotics. 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Nat Rev Mol Cell Biol 9, 242\u2013253 (2008).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_3_4_6_2","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1128\/AAC.01550-10","article-title":"Molecular detection of mutations associated with first and second-line drug resistance compared with conventional drug susceptibility testing in M. tuberculosis","volume":"55","author":"Campbell PJ","year":"2011","unstructured":"PJ Campbell, et al., Molecular detection of mutations associated with first and second-line drug resistance compared with conventional drug susceptibility testing in M. tuberculosis. Antimicrob Agents Chemother 55, 2032\u20132041 (2011).","journal-title":"Antimicrob Agents Chemother"},{"key":"e_1_3_4_7_2","doi-asserted-by":"crossref","first-page":"20004","DOI":"10.1073\/pnas.0907925106","article-title":"Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis","volume":"106","author":"Zaunbrecher MA","year":"2009","unstructured":"MA Zaunbrecher, RD Sikes, B Metchock, TM Shinnick, JE Posey, Overexpression of the chromosomally encoded aminoglycoside acetyltransferase eis confers kanamycin resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci USA 106, 20004\u201320009 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nsb830","article-title":"Aminoglycoside 2\u2032-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates","volume":"9","author":"Vetting MW","year":"2002","unstructured":"MW Vetting, SS Hegde, F Javid-Majd, JS Blanchard, SL Roderick, Aminoglycoside 2\u2032-N-acetyltransferase from Mycobacterium tuberculosis in complex with coenzyme A and aminoglycoside substrates. Nat Struct Biol 9, 653\u2013658 (2002).","journal-title":"Nat Struct Biol"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"45876","DOI":"10.1074\/jbc.M108810200","article-title":"Overexpression and mechanistic analysis of chromosomally encoded aminoglycoside 2\u2032-N-acetyltransferase (AAC(2\u2032)-Ic) from Mycobacterium tuberculosis","volume":"276","author":"Hegde SS","year":"2001","unstructured":"SS Hegde, F Javid-Majd, JS Blanchard, Overexpression and mechanistic analysis of chromosomally encoded aminoglycoside 2\u2032-N-acetyltransferase (AAC(2\u2032)-Ic) from Mycobacterium tuberculosis. J Biol Chem 276, 45876\u201345881 (2001).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/cbic.200900584","article-title":"Exploring the substrate promiscuity of drug-modifying enzymes for the chemoenzymatic generation of N-acylated aminoglycosides","volume":"11","author":"Green KD","year":"2010","unstructured":"KD Green, W Chen, JL Houghton, M Fridman, S Garneau-Tsodikova, Exploring the substrate promiscuity of drug-modifying enzymes for the chemoenzymatic generation of N-acylated aminoglycosides. 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Biochim Biophys Acta 1441, 162\u2013172 (1999).","journal-title":"Biochim Biophys Acta"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1128\/JB.182.2.377-384.2000","article-title":"Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages","volume":"182","author":"Wei J","year":"2000","unstructured":"J Wei, et al., Identification of a Mycobacterium tuberculosis gene that enhances mycobacterial survival in macrophages. J Bacteriol 182, 377\u2013384 (2000).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","first-page":"4295","DOI":"10.1128\/IAI.69.7.4295-4302.2001","article-title":"Subcellular localization of the Iitracellular survival-enhancing Eis protein of Mycobacterium tuberculosis","volume":"69","author":"Dahl JL","year":"2001","unstructured":"JL Dahl, J Wei, JW Moulder, S Laal, RL Friedman, Subcellular localization of the Iitracellular survival-enhancing Eis protein of Mycobacterium tuberculosis. Infect Immun 69, 4295\u20134302 (2001).","journal-title":"Infect Immun"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","first-page":"5410","DOI":"10.1128\/JB.186.16.5410-5417.2004","article-title":"Molecular characterization of the eis promoter of Mycobacterium tuberculosis","volume":"186","author":"Roberts EA","year":"2004","unstructured":"EA Roberts, A Clark, S McBeth, RL Friedman, Molecular characterization of the eis promoter of Mycobacterium tuberculosis. J Bacteriol 186, 5410\u20135417 (2004).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_25_2","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1128\/JB.187.7.2439-2447.2005","article-title":"The relA homolog of Mycobacterium smegmatis affects cell appearance, viability, and gene expression","volume":"187","author":"Dahl JL","year":"2005","unstructured":"JL Dahl, et al., The relA homolog of Mycobacterium smegmatis affects cell appearance, viability, and gene expression. J Bacteriol 187, 2439\u20132447 (2005).","journal-title":"J Bacteriol"},{"key":"e_1_3_4_26_2","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1099\/mic.0.2006\/002642-0","article-title":"Expression, production, and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion","volume":"153","author":"Samuel LP","year":"2007","unstructured":"LP Samuel, et al., Expression, production, and release of the Eis protein by Mycobacterium tuberculosis during infection of macrophages and its effect on cytokine secretion. Microbiology 153, 529\u2013540 (2007).","journal-title":"Microbiology"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","first-page":"18671","DOI":"10.1074\/jbc.C600280200","article-title":"Eis (enhanced intracellular survival) protein of Mycobacterium tuberculosis disturbs the cross regulation of T-cells","volume":"282","author":"Lella RK","year":"2007","unstructured":"RK Lella, C Sharma, Eis (enhanced intracellular survival) protein of Mycobacterium tuberculosis disturbs the cross regulation of T-cells. J Biol Chem 282, 18671\u201318675 (2007).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1099\/mic.0.024638-0","article-title":"Activation of the eis gene in a W-Beijing strain of Mycobacterium tuberculosis correlates with increased SigA levels and enhanced intracellular growth","volume":"155","author":"Wu S","year":"2009","unstructured":"S Wu, et al., Activation of the eis gene in a W-Beijing strain of Mycobacterium tuberculosis correlates with increased SigA levels and enhanced intracellular growth. Microbiology 155, 1272\u20131281 (2009).","journal-title":"Microbiology"},{"key":"e_1_3_4_29_2","doi-asserted-by":"crossref","first-page":"e1001230","DOI":"10.1371\/journal.ppat.1001230","article-title":"Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling","volume":"6","author":"Shin DM","year":"2010","unstructured":"DM Shin, et al., Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. PLoS Pathog 6, e1001230 (2010).","journal-title":"PLoS Pathog"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1105379108","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T03:31:42Z","timestamp":1654572702000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1105379108"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,5,31]]},"references-count":29,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2011,6,14]]}},"alternative-id":["10.1073\/pnas.1105379108"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1105379108","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,5,31]]},"assertion":[{"value":"2011-05-31","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}