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However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2\u2032)-Ia from <jats:italic>Providencia stuartii<\/jats:italic>. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2\u2032)-Ia from <jats:italic>P. stuartii<\/jats:italic>, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2\u2032)-Ia-acetylated plazomicin complex, these structures outline AAC(2\u2032)-Ia\u2019s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2\u2032)-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.<\/jats:p>","DOI":"10.1038\/s41598-021-89446-3","type":"journal-article","created":{"date-parts":[[2021,6,2]],"date-time":"2021-06-02T10:08:04Z","timestamp":1622628484000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2\u2032) enzymes"],"prefix":"10.1038","volume":"11","author":[{"given":"Angelia V.","family":"Bassenden","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Dumalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaeok","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Blanchet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishnagopal","family":"Maiti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dev P.","family":"Arya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert M.","family":"Berghuis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,6,2]]},"reference":[{"key":"89446_CR1","doi-asserted-by":"publisher","DOI":"10.1002\/9780470149676","volume-title":"Aminoglycoside antibiotics: From chemical biology to drug discovery","author":"DP Arya","year":"2007","unstructured":"Arya, D. 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