Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes

Abstract Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stu...

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Autores principales:	Angelia V. Bassenden, Linda Dumalo, Jaeok Park, Jonathan Blanchet, Krishnagopal Maiti, Dev P. Arya, Albert M. Berghuis
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a0c86b251ae74d7bb3c137708fa1bbd2
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spelling	oai:doaj.org-article:a0c86b251ae74d7bb3c137708fa1bbd22021-12-02T15:56:57ZStructural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes10.1038/s41598-021-89446-32045-2322https://doaj.org/article/a0c86b251ae74d7bb3c137708fa1bbd22021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89446-3https://doaj.org/toc/2045-2322Abstract Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stuartii. 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′)-Ia from P. stuartii, 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′)-Ia-acetylated plazomicin complex, these structures outline AAC(2′)-Ia’s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2′)-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.Angelia V. BassendenLinda DumaloJaeok ParkJonathan BlanchetKrishnagopal MaitiDev P. AryaAlbert M. BerghuisNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Angelia V. Bassenden Linda Dumalo Jaeok Park Jonathan Blanchet Krishnagopal Maiti Dev P. Arya Albert M. Berghuis Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
description	Abstract Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2′)-Ia from Providencia stuartii. 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′)-Ia from P. stuartii, 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′)-Ia-acetylated plazomicin complex, these structures outline AAC(2′)-Ia’s specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2′)-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.
format	article
author	Angelia V. Bassenden Linda Dumalo Jaeok Park Jonathan Blanchet Krishnagopal Maiti Dev P. Arya Albert M. Berghuis
author_facet	Angelia V. Bassenden Linda Dumalo Jaeok Park Jonathan Blanchet Krishnagopal Maiti Dev P. Arya Albert M. Berghuis
author_sort	Angelia V. Bassenden
title	Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
title_short	Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
title_full	Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
title_fullStr	Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
title_full_unstemmed	Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes
title_sort	structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by aac(2′) enzymes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a0c86b251ae74d7bb3c137708fa1bbd2
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Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2′) enzymes

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