Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism

ABSTRACT Staphylococcus aureus infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	William N. Beavers, Andrew J. Monteith, Venkataraman Amarnath, Raymond L. Mernaugh, L. Jackson Roberts, Walter J. Chazin, Sean S. Davies, Eric P. Skaar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	isolevuglandins arachidonic acid MRSA pathogenesis polyunsaturated fatty acids Staphylococcus aureus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/8d48f172b9184d079ef7539080bca2d8
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:8d48f172b9184d079ef7539080bca2d8
record_format	dspace
spelling	oai:doaj.org-article:8d48f172b9184d079ef7539080bca2d82021-11-15T15:59:41ZArachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism10.1128/mBio.01333-192150-7511https://doaj.org/article/8d48f172b9184d079ef7539080bca2d82019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01333-19https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which are highly abundant in eukaryotes and encountered by S. aureus at the host-pathogen interface. Arachidonic acid (AA) is one of the most abundant polyunsaturated fatty acids in vertebrates and is released in large amounts during the oxidative burst. Most of the released AA is converted to bioactive signaling molecules, but, independently of its role in inflammatory signaling, AA is toxic to S. aureus. Here, we report that AA kills S. aureus through a lipid peroxidation mechanism whereby AA is oxidized to reactive electrophiles that modify S. aureus macromolecules, eliciting toxicity. This process is rescued by cotreatment with antioxidants as well as in a S. aureus strain genetically inactivated for lcpA (USA300 ΔlcpA mutant) that produces lower levels of reactive oxygen species. However, resistance to AA stress in the USA300 ΔlcpA mutant comes at a cost, making the mutant more susceptible to β-lactam antibiotics and attenuated for pathogenesis in a murine infection model compared to the parental methicillin-resistant S. aureus (MRSA) strain, indicating that resistance to AA toxicity increases susceptibility to other stressors encountered during infection. This report defines the mechanism by which AA is toxic to S. aureus and identifies lipid peroxidation as a pathway that can be modulated for the development of future therapeutics to treat S. aureus infections. IMPORTANCE Despite the ability of the human immune system to generate a plethora of molecules to control Staphylococcus aureus infections, S. aureus is among the pathogens with the greatest impact on human health. One class of host molecules toxic to S. aureus consists of polyunsaturated fatty acids. Here, we investigated the antibacterial properties of arachidonic acid, one of the most abundant polyunsaturated fatty acids in humans, and discovered that the mechanism of toxicity against S. aureus proceeds through lipid peroxidation. A better understanding of the molecular mechanisms by which the immune system kills S. aureus, and by which S. aureus avoids host killing, will enable the optimal design of therapeutics that complement the ability of the vertebrate immune response to eliminate S. aureus infections.William N. BeaversAndrew J. MonteithVenkataraman AmarnathRaymond L. MernaughL. Jackson RobertsWalter J. ChazinSean S. DaviesEric P. SkaarAmerican Society for Microbiologyarticleisolevuglandinsarachidonic acidMRSApathogenesispolyunsaturated fatty acidsStaphylococcus aureusMicrobiologyQR1-502ENmBio, Vol 10, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	isolevuglandins arachidonic acid MRSA pathogenesis polyunsaturated fatty acids Staphylococcus aureus Microbiology QR1-502
spellingShingle	isolevuglandins arachidonic acid MRSA pathogenesis polyunsaturated fatty acids Staphylococcus aureus Microbiology QR1-502 William N. Beavers Andrew J. Monteith Venkataraman Amarnath Raymond L. Mernaugh L. Jackson Roberts Walter J. Chazin Sean S. Davies Eric P. Skaar Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
description	ABSTRACT Staphylococcus aureus infects every niche of the human host. In response to microbial infection, vertebrates have an arsenal of antimicrobial compounds that inhibit bacterial growth or kill bacterial cells. One class of antimicrobial compounds consists of polyunsaturated fatty acids, which are highly abundant in eukaryotes and encountered by S. aureus at the host-pathogen interface. Arachidonic acid (AA) is one of the most abundant polyunsaturated fatty acids in vertebrates and is released in large amounts during the oxidative burst. Most of the released AA is converted to bioactive signaling molecules, but, independently of its role in inflammatory signaling, AA is toxic to S. aureus. Here, we report that AA kills S. aureus through a lipid peroxidation mechanism whereby AA is oxidized to reactive electrophiles that modify S. aureus macromolecules, eliciting toxicity. This process is rescued by cotreatment with antioxidants as well as in a S. aureus strain genetically inactivated for lcpA (USA300 ΔlcpA mutant) that produces lower levels of reactive oxygen species. However, resistance to AA stress in the USA300 ΔlcpA mutant comes at a cost, making the mutant more susceptible to β-lactam antibiotics and attenuated for pathogenesis in a murine infection model compared to the parental methicillin-resistant S. aureus (MRSA) strain, indicating that resistance to AA toxicity increases susceptibility to other stressors encountered during infection. This report defines the mechanism by which AA is toxic to S. aureus and identifies lipid peroxidation as a pathway that can be modulated for the development of future therapeutics to treat S. aureus infections. IMPORTANCE Despite the ability of the human immune system to generate a plethora of molecules to control Staphylococcus aureus infections, S. aureus is among the pathogens with the greatest impact on human health. One class of host molecules toxic to S. aureus consists of polyunsaturated fatty acids. Here, we investigated the antibacterial properties of arachidonic acid, one of the most abundant polyunsaturated fatty acids in humans, and discovered that the mechanism of toxicity against S. aureus proceeds through lipid peroxidation. A better understanding of the molecular mechanisms by which the immune system kills S. aureus, and by which S. aureus avoids host killing, will enable the optimal design of therapeutics that complement the ability of the vertebrate immune response to eliminate S. aureus infections.
format	article
author	William N. Beavers Andrew J. Monteith Venkataraman Amarnath Raymond L. Mernaugh L. Jackson Roberts Walter J. Chazin Sean S. Davies Eric P. Skaar
author_facet	William N. Beavers Andrew J. Monteith Venkataraman Amarnath Raymond L. Mernaugh L. Jackson Roberts Walter J. Chazin Sean S. Davies Eric P. Skaar
author_sort	William N. Beavers
title	Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
title_short	Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
title_full	Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
title_fullStr	Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
title_full_unstemmed	Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism
title_sort	arachidonic acid kills <named-content content-type="genus-species">staphylococcus aureus</named-content> through a lipid peroxidation mechanism
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/8d48f172b9184d079ef7539080bca2d8
work_keys_str_mv	AT williamnbeavers arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT andrewjmonteith arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT venkataramanamarnath arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT raymondlmernaugh arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT ljacksonroberts arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT walterjchazin arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT seansdavies arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism AT ericpskaar arachidonicacidkillsnamedcontentcontenttypegenusspeciesstaphylococcusaureusnamedcontentthroughalipidperoxidationmechanism
_version_	1718426980360126464

Arachidonic Acid Kills <named-content content-type="genus-species">Staphylococcus aureus</named-content> through a Lipid Peroxidation Mechanism

Ejemplares similares