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It has developed numerous strategies to overcome the antibiotic stress response, limiting treatment options and leading to frequent therapeutic failure. The panel of aminoglycosides (<jats:styled-content style=\"fixed-case\">AG<\/jats:styled-content>) usually used in the treatment of <jats:italic>M.\u00a0abscessus<\/jats:italic> pulmonary infections is restricted by chemical modification of the drugs by the <jats:italic>N<\/jats:italic>\u2010acetyltransferase Eis2 protein (<jats:italic>Mabs<\/jats:italic>_Eis2). This enzyme acetylates the primary amine of <jats:styled-content style=\"fixed-case\">AG<\/jats:styled-content>s, preventing these antibiotics from binding ribosomal <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> and thereby impairing their activity. In this study, the high\u2010resolution crystal structures of <jats:italic>Mabs<\/jats:italic>_Eis2 in its <jats:italic>apo<\/jats:italic>\u2010 and cofactor\u2010bound forms were solved. The structural analysis of <jats:italic>Mabs<\/jats:italic>_Eis2, supported by the kinetic characterization of the enzyme, highlights the large substrate specificity of the enzyme. Furthermore, <jats:italic>in\u00a0silico<\/jats:italic> docking and biochemical approaches attest that <jats:italic>Mabs<\/jats:italic>_Eis2 modifies clinically relevant drugs such as kanamycin and amikacin, with a better efficacy for the latter. In line with previous biochemical and <jats:italic>in\u00a0vivo<\/jats:italic> studies, our work suggests that <jats:italic>Mabs<\/jats:italic>_Eis2 represents an attractive pharmacological target to be further explored. The high\u2010resolution crystal structures presented here may pave the way to the design of Eis2\u2010specific inhibitors with the potential to counteract the intrinsic resistance levels of <jats:italic>M.\u00a0abscessus<\/jats:italic> to an important class of clinically important antibiotics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Database<\/jats:title><jats:p>Structural data are available in the <jats:styled-content style=\"fixed-case\">PDB<\/jats:styled-content> database under the accession numbers: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=6RFY\">6RFY<\/jats:ext-link>, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=6RFX \">6RFX<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=6RFT\">6RFT<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.14975","type":"journal-article","created":{"date-parts":[[2019,6,29]],"date-time":"2019-06-29T14:09:29Z","timestamp":1561817369000},"page":"4342-4355","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Crystal structure of the aminoglycosides <i>N<\/i>\u2010acetyltransferase Eis2 from <i>Mycobacterium\u00a0abscessus<\/i>"],"prefix":"10.1111","volume":"286","author":[{"given":"Kien Lam","family":"Ung","sequence":"first","affiliation":[{"name":"Institut de Recherche en Infectiologie de Montpellier (IRIM) CNRS UMR 9004 Universit\u00e9 de Montpellier France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Husam M. 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