Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module

ABSTRACT Resistance to the lantibiotic nisin (NIS) arises readily in Staphylococcus aureus as a consequence of mutations in the nsaS gene, which encodes the sensor kinase of the NsaRS two-component regulatory system. Here we present a series of studies to establish how these mutational changes resul...

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Autores principales:	Christopher P. Randall, Arya Gupta, Bret Utley-Drew, Siu Yi Lee, Genevieve Morrison-Williams, Alex J. O’Neill
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	bacteriocin lantibiotic resistance studies staphylococci Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9b03415a9c534106a0f35536e02051d2
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spelling	oai:doaj.org-article:9b03415a9c534106a0f35536e02051d22021-11-15T15:22:21ZAcquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module10.1128/mSphereDirect.00633-182379-5042https://doaj.org/article/9b03415a9c534106a0f35536e02051d22018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphereDirect.00633-18https://doaj.org/toc/2379-5042ABSTRACT Resistance to the lantibiotic nisin (NIS) arises readily in Staphylococcus aureus as a consequence of mutations in the nsaS gene, which encodes the sensor kinase of the NsaRS two-component regulatory system. Here we present a series of studies to establish how these mutational changes result in reduced NIS susceptibility. Comparative transcriptomic analysis revealed upregulation of the NsaRS regulon in a NIS-resistant mutant of S. aureus versus its otherwise-isogenic progenitor, indicating that NIS resistance mutations prompt gain-of-function in NsaS. Two putative ABC transporters (BraDE and VraDE) encoded within the NsaRS regulon that have been reported to provide a degree of intrinsic protection against NIS were shown to be responsible for acquired NIS resistance; as is the case for intrinsic NIS resistance, NIS detoxification was ultimately mediated by VraDE, with BraDE participating in the signaling cascade underlying VraDE expression. Our study revealed new features of this signal transduction pathway, including that BraDE (but not VraDE) physically interacts with NsaRS. Furthermore, while BraDE has been shown to sense stimuli and signal to NsaS in a process that is contingent upon ATP hydrolysis, we established that this protein complex is also essential for onward transduction of the signal from NsaS through energy-independent means. NIS resistance in S. aureus therefore joins the small number of documented examples in which acquired antimicrobial resistance results from the unmasking of an intrinsic detoxification mechanism through gain-of-function mutation in a regulatory circuit. IMPORTANCE NIS and related bacteriocins are of interest as candidates for the treatment of human infections caused by Gram-positive pathogens such as Staphylococcus aureus. An important liability of NIS in this regard is the ease with which S. aureus acquires resistance. Here we establish that this organism naturally possesses the cellular machinery to detoxify NIS but that the ABC transporter responsible (VraDE) is not ordinarily produced to a degree sufficient to yield substantial resistance. Acquired NIS resistance mutations prompt activation of the regulatory circuit controlling expression of vraDE, thereby unmasking an intrinsic resistance determinant. Our results provide new insights into the complex mechanism by which expression of vraDE is regulated and suggest that a potential route to overcoming the resistance liability of NIS could involve chemical modification of the molecule to prevent its recognition by the VraDE transporter.Christopher P. RandallArya GuptaBret Utley-DrewSiu Yi LeeGenevieve Morrison-WilliamsAlex J. O’NeillAmerican Society for Microbiologyarticlebacteriocinlantibioticresistance studiesstaphylococciMicrobiologyQR1-502ENmSphere, Vol 3, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	bacteriocin lantibiotic resistance studies staphylococci Microbiology QR1-502
spellingShingle	bacteriocin lantibiotic resistance studies staphylococci Microbiology QR1-502 Christopher P. Randall Arya Gupta Bret Utley-Drew Siu Yi Lee Genevieve Morrison-Williams Alex J. O’Neill Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
description	ABSTRACT Resistance to the lantibiotic nisin (NIS) arises readily in Staphylococcus aureus as a consequence of mutations in the nsaS gene, which encodes the sensor kinase of the NsaRS two-component regulatory system. Here we present a series of studies to establish how these mutational changes result in reduced NIS susceptibility. Comparative transcriptomic analysis revealed upregulation of the NsaRS regulon in a NIS-resistant mutant of S. aureus versus its otherwise-isogenic progenitor, indicating that NIS resistance mutations prompt gain-of-function in NsaS. Two putative ABC transporters (BraDE and VraDE) encoded within the NsaRS regulon that have been reported to provide a degree of intrinsic protection against NIS were shown to be responsible for acquired NIS resistance; as is the case for intrinsic NIS resistance, NIS detoxification was ultimately mediated by VraDE, with BraDE participating in the signaling cascade underlying VraDE expression. Our study revealed new features of this signal transduction pathway, including that BraDE (but not VraDE) physically interacts with NsaRS. Furthermore, while BraDE has been shown to sense stimuli and signal to NsaS in a process that is contingent upon ATP hydrolysis, we established that this protein complex is also essential for onward transduction of the signal from NsaS through energy-independent means. NIS resistance in S. aureus therefore joins the small number of documented examples in which acquired antimicrobial resistance results from the unmasking of an intrinsic detoxification mechanism through gain-of-function mutation in a regulatory circuit. IMPORTANCE NIS and related bacteriocins are of interest as candidates for the treatment of human infections caused by Gram-positive pathogens such as Staphylococcus aureus. An important liability of NIS in this regard is the ease with which S. aureus acquires resistance. Here we establish that this organism naturally possesses the cellular machinery to detoxify NIS but that the ABC transporter responsible (VraDE) is not ordinarily produced to a degree sufficient to yield substantial resistance. Acquired NIS resistance mutations prompt activation of the regulatory circuit controlling expression of vraDE, thereby unmasking an intrinsic resistance determinant. Our results provide new insights into the complex mechanism by which expression of vraDE is regulated and suggest that a potential route to overcoming the resistance liability of NIS could involve chemical modification of the molecule to prevent its recognition by the VraDE transporter.
format	article
author	Christopher P. Randall Arya Gupta Bret Utley-Drew Siu Yi Lee Genevieve Morrison-Williams Alex J. O’Neill
author_facet	Christopher P. Randall Arya Gupta Bret Utley-Drew Siu Yi Lee Genevieve Morrison-Williams Alex J. O’Neill
author_sort	Christopher P. Randall
title	Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
title_short	Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
title_full	Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
title_fullStr	Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
title_full_unstemmed	Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module
title_sort	acquired nisin resistance in <italic toggle="yes">staphylococcus aureus</italic> involves constitutive activation of an intrinsic peptide antibiotic detoxification module
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/9b03415a9c534106a0f35536e02051d2
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Acquired Nisin Resistance in <italic toggle="yes">Staphylococcus aureus</italic> Involves Constitutive Activation of an Intrinsic Peptide Antibiotic Detoxification Module

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