Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins

ABSTRACT Staphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we s...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Martin Vestergaard, Katrine Nøhr-Meldgaard, Martin Saxtorph Bojer, Christina Krogsgård Nielsen, Rikke Louise Meyer, Christoph Slavetinsky, Andreas Peschel, Hanne Ingmer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	ATP synthase Staphylococcus aureus antimicrobial peptides atpA intrinsic resistance oligomycin A Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4070bcfecf0543d99c2c514279899795
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4070bcfecf0543d99c2c514279899795
record_format	dspace
spelling	oai:doaj.org-article:4070bcfecf0543d99c2c5142798997952021-11-15T15:51:50ZInhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins10.1128/mBio.01114-172150-7511https://doaj.org/article/4070bcfecf0543d99c2c5142798997952017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01114-17https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we screened the Nebraska Transposon Mutant Library established in S. aureus strain JE2 for increased susceptibility to polymyxin B. Nineteen mutants displayed at least 2-fold reductions in MIC, while the greatest reductions (8-fold) were observed for mutants with inactivation of either graS, graR, vraF, or vraG or the subunits of the ATP synthase (atpA, atpB, atpG, or atpH), which during respiration is the main source of energy. Inactivation of atpA also conferred hypersusceptibility to colistin and the aminoglycoside gentamicin, whereas susceptibilities to nisin, gallidermin, bacitracin, vancomycin, ciprofloxacin, linezolid, daptomycin, and oxacillin were unchanged. ATP synthase activity is known to be inhibited by oligomycin A, and the presence of this compound increased polymyxin B-mediated killing of S. aureus. Our results demonstrate that the ATP synthase contributes to intrinsic resistance of S. aureus towards polymyxins and that inhibition of the ATP synthase sensitizes S. aureus to this group of compounds. These findings show that by modulation of bacterial metabolism, new classes of antibiotics may show efficacy against pathogens towards which they were previously considered inapplicable. In light of the need for new treatment options for infections with serious pathogens like S. aureus, this approach may pave the way for novel applications of existing antibiotics. IMPORTANCE Bacterial pathogens that cause disease in humans remain a serious threat to public health, and antibiotics are still our primary weapon in treating bacterial diseases. The ability to eradicate bacterial infections is critically challenged by development of resistance to all clinically available antibiotics. Polymyxins constitute an important class of antibiotics for treatment of infections caused by Gram-negative pathogens, whereas Gram-positive bacteria remain largely insusceptible towards class of antibiotics. Here we performed a whole-genome screen among nonessential genes for polymyxin intrinsic resistance determinants in Staphylococcus aureus. We found that the ATP synthase is important for polymyxin susceptibility and that inhibition of the ATP synthase sensitizes S. aureus towards polymyxins. Our study provides novel insights into the mechanisms that limit polymyxin activity against S. aureus and provides valuable targets for inhibitors to potentially enable the use of polymyxins against S. aureus and other Gram-positive pathogens.Martin VestergaardKatrine Nøhr-MeldgaardMartin Saxtorph BojerChristina Krogsgård NielsenRikke Louise MeyerChristoph SlavetinskyAndreas PeschelHanne IngmerAmerican Society for MicrobiologyarticleATP synthaseStaphylococcus aureusantimicrobial peptidesatpAintrinsic resistanceoligomycin AMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP synthase Staphylococcus aureus antimicrobial peptides atpA intrinsic resistance oligomycin A Microbiology QR1-502
spellingShingle	ATP synthase Staphylococcus aureus antimicrobial peptides atpA intrinsic resistance oligomycin A Microbiology QR1-502 Martin Vestergaard Katrine Nøhr-Meldgaard Martin Saxtorph Bojer Christina Krogsgård Nielsen Rikke Louise Meyer Christoph Slavetinsky Andreas Peschel Hanne Ingmer Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
description	ABSTRACT Staphylococcus aureus is intrinsically resistant to polymyxins (polymyxin B and colistin), an important class of cationic antimicrobial peptides used in treatment of Gram-negative bacterial infections. To understand the mechanisms underlying intrinsic polymyxin resistance in S. aureus, we screened the Nebraska Transposon Mutant Library established in S. aureus strain JE2 for increased susceptibility to polymyxin B. Nineteen mutants displayed at least 2-fold reductions in MIC, while the greatest reductions (8-fold) were observed for mutants with inactivation of either graS, graR, vraF, or vraG or the subunits of the ATP synthase (atpA, atpB, atpG, or atpH), which during respiration is the main source of energy. Inactivation of atpA also conferred hypersusceptibility to colistin and the aminoglycoside gentamicin, whereas susceptibilities to nisin, gallidermin, bacitracin, vancomycin, ciprofloxacin, linezolid, daptomycin, and oxacillin were unchanged. ATP synthase activity is known to be inhibited by oligomycin A, and the presence of this compound increased polymyxin B-mediated killing of S. aureus. Our results demonstrate that the ATP synthase contributes to intrinsic resistance of S. aureus towards polymyxins and that inhibition of the ATP synthase sensitizes S. aureus to this group of compounds. These findings show that by modulation of bacterial metabolism, new classes of antibiotics may show efficacy against pathogens towards which they were previously considered inapplicable. In light of the need for new treatment options for infections with serious pathogens like S. aureus, this approach may pave the way for novel applications of existing antibiotics. IMPORTANCE Bacterial pathogens that cause disease in humans remain a serious threat to public health, and antibiotics are still our primary weapon in treating bacterial diseases. The ability to eradicate bacterial infections is critically challenged by development of resistance to all clinically available antibiotics. Polymyxins constitute an important class of antibiotics for treatment of infections caused by Gram-negative pathogens, whereas Gram-positive bacteria remain largely insusceptible towards class of antibiotics. Here we performed a whole-genome screen among nonessential genes for polymyxin intrinsic resistance determinants in Staphylococcus aureus. We found that the ATP synthase is important for polymyxin susceptibility and that inhibition of the ATP synthase sensitizes S. aureus towards polymyxins. Our study provides novel insights into the mechanisms that limit polymyxin activity against S. aureus and provides valuable targets for inhibitors to potentially enable the use of polymyxins against S. aureus and other Gram-positive pathogens.
format	article
author	Martin Vestergaard Katrine Nøhr-Meldgaard Martin Saxtorph Bojer Christina Krogsgård Nielsen Rikke Louise Meyer Christoph Slavetinsky Andreas Peschel Hanne Ingmer
author_facet	Martin Vestergaard Katrine Nøhr-Meldgaard Martin Saxtorph Bojer Christina Krogsgård Nielsen Rikke Louise Meyer Christoph Slavetinsky Andreas Peschel Hanne Ingmer
author_sort	Martin Vestergaard
title	Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
title_short	Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
title_full	Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
title_fullStr	Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
title_full_unstemmed	Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins
title_sort	inhibition of the atp synthase eliminates the intrinsic resistance of <italic toggle="yes">staphylococcus aureus</italic> towards polymyxins
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/4070bcfecf0543d99c2c514279899795
work_keys_str_mv	AT martinvestergaard inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT katrinenøhrmeldgaard inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT martinsaxtorphbojer inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT christinakrogsgardnielsen inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT rikkelouisemeyer inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT christophslavetinsky inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT andreaspeschel inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins AT hanneingmer inhibitionoftheatpsynthaseeliminatestheintrinsicresistanceofitalictoggleyesstaphylococcusaureusitalictowardspolymyxins
_version_	1718427329233944576

Inhibition of the ATP Synthase Eliminates the Intrinsic Resistance of <italic toggle="yes">Staphylococcus aureus</italic> towards Polymyxins

Ejemplares similares