Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site

ABSTRACT Staphylococcus aureus utilizes the fatty acid (FA) kinase system to activate exogenous FAs for membrane synthesis. We developed a lipidomics workflow to determine the membrane phosphatidylglycerol (PG) molecular species synthesized by S. aureus at the thigh infection site. Wild-type S. aure...

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Autores principales:	Matthew W. Frank, Jiangwei Yao, Justin L. Batte, Jessica M. Gullett, Chitra Subramanian, Jason W. Rosch, Charles O. Rock
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Staphylococcus aureus fatty acid fatty acid kinase fatty acid binding protein phospholipid virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/c0ca964bc43b49d1a868f31ece6173e2
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spelling	oai:doaj.org-article:c0ca964bc43b49d1a868f31ece6173e22021-11-15T15:56:47ZHost Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site10.1128/mBio.00920-202150-7511https://doaj.org/article/c0ca964bc43b49d1a868f31ece6173e22020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00920-20https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus utilizes the fatty acid (FA) kinase system to activate exogenous FAs for membrane synthesis. We developed a lipidomics workflow to determine the membrane phosphatidylglycerol (PG) molecular species synthesized by S. aureus at the thigh infection site. Wild-type S. aureus utilizes both host palmitate and oleate to acylate the 1 position of PG, and the 2 position is occupied by pentadecanoic acid arising from de novo biosynthesis. Inactivation of FakB2 eliminates the ability to assimilate oleate and inactivation of FakB1 reduces the content of saturated FAs and enhances oleate utilization. Elimination of FA activation in either ΔfakA or ΔfakB1 ΔfakB2 mutants does not impact growth. All S. aureus strains recovered from the thigh have significantly reduced branched-chain FAs and increased even-chain FAs compared to that with growth in rich laboratory medium. The molecular species pattern observed in the thigh was reproduced in the laboratory by growth in isoleucine-deficient medium containing exogenous FAs. S. aureus utilizes specific host FAs for membrane biosynthesis but also requires de novo FA biosynthesis initiated by isoleucine (or leucine) to produce pentadecanoic acid. IMPORTANCE The shortage of antibiotics against drug-resistant Staphylococcus aureus has led to the development of new drugs targeting the elongation cycle of fatty acid (FA) synthesis that are progressing toward the clinic. An objection to the use of FA synthesis inhibitors is that S. aureus can utilize exogenous FAs to construct its membrane, suggesting that the bacterium would bypass these therapeutics by utilizing host FAs instead. We developed a mass spectrometry workflow to determine the composition of the S. aureus membrane at the infection site to directly address how S. aureus uses host FAs. S. aureus strains that cannot acquire host FAs are as effective in establishing an infection as the wild type, but strains that require the utilization of host FAs for growth were attenuated in the mouse thigh infection model. We find that S. aureus does utilize host FAs to construct its membrane, but host FAs do not replace the requirement for pentadecanoic acid, a branched-chain FA derived from isoleucine (or leucine) that predominantly occupies the 2 position of S. aureus phospholipids. The membrane phospholipid structure of S. aureus mutants that cannot utilize host FAs indicates the isoleucine is a scarce resource at the infection site. This reliance on the de novo synthesis of predominantly pentadecanoic acid that cannot be obtained from the host is one reason why drugs that target fatty acid synthesis are effective in treating S. aureus infections.Matthew W. FrankJiangwei YaoJustin L. BatteJessica M. GullettChitra SubramanianJason W. RoschCharles O. RockAmerican Society for MicrobiologyarticleStaphylococcus aureusfatty acidfatty acid kinasefatty acid binding proteinphospholipidvirulenceMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus fatty acid fatty acid kinase fatty acid binding protein phospholipid virulence Microbiology QR1-502
spellingShingle	Staphylococcus aureus fatty acid fatty acid kinase fatty acid binding protein phospholipid virulence Microbiology QR1-502 Matthew W. Frank Jiangwei Yao Justin L. Batte Jessica M. Gullett Chitra Subramanian Jason W. Rosch Charles O. Rock Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
description	ABSTRACT Staphylococcus aureus utilizes the fatty acid (FA) kinase system to activate exogenous FAs for membrane synthesis. We developed a lipidomics workflow to determine the membrane phosphatidylglycerol (PG) molecular species synthesized by S. aureus at the thigh infection site. Wild-type S. aureus utilizes both host palmitate and oleate to acylate the 1 position of PG, and the 2 position is occupied by pentadecanoic acid arising from de novo biosynthesis. Inactivation of FakB2 eliminates the ability to assimilate oleate and inactivation of FakB1 reduces the content of saturated FAs and enhances oleate utilization. Elimination of FA activation in either ΔfakA or ΔfakB1 ΔfakB2 mutants does not impact growth. All S. aureus strains recovered from the thigh have significantly reduced branched-chain FAs and increased even-chain FAs compared to that with growth in rich laboratory medium. The molecular species pattern observed in the thigh was reproduced in the laboratory by growth in isoleucine-deficient medium containing exogenous FAs. S. aureus utilizes specific host FAs for membrane biosynthesis but also requires de novo FA biosynthesis initiated by isoleucine (or leucine) to produce pentadecanoic acid. IMPORTANCE The shortage of antibiotics against drug-resistant Staphylococcus aureus has led to the development of new drugs targeting the elongation cycle of fatty acid (FA) synthesis that are progressing toward the clinic. An objection to the use of FA synthesis inhibitors is that S. aureus can utilize exogenous FAs to construct its membrane, suggesting that the bacterium would bypass these therapeutics by utilizing host FAs instead. We developed a mass spectrometry workflow to determine the composition of the S. aureus membrane at the infection site to directly address how S. aureus uses host FAs. S. aureus strains that cannot acquire host FAs are as effective in establishing an infection as the wild type, but strains that require the utilization of host FAs for growth were attenuated in the mouse thigh infection model. We find that S. aureus does utilize host FAs to construct its membrane, but host FAs do not replace the requirement for pentadecanoic acid, a branched-chain FA derived from isoleucine (or leucine) that predominantly occupies the 2 position of S. aureus phospholipids. The membrane phospholipid structure of S. aureus mutants that cannot utilize host FAs indicates the isoleucine is a scarce resource at the infection site. This reliance on the de novo synthesis of predominantly pentadecanoic acid that cannot be obtained from the host is one reason why drugs that target fatty acid synthesis are effective in treating S. aureus infections.
format	article
author	Matthew W. Frank Jiangwei Yao Justin L. Batte Jessica M. Gullett Chitra Subramanian Jason W. Rosch Charles O. Rock
author_facet	Matthew W. Frank Jiangwei Yao Justin L. Batte Jessica M. Gullett Chitra Subramanian Jason W. Rosch Charles O. Rock
author_sort	Matthew W. Frank
title	Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
title_short	Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
title_full	Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
title_fullStr	Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
title_full_unstemmed	Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site
title_sort	host fatty acid utilization by <named-content content-type="genus-species">staphylococcus aureus</named-content> at the infection site
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/c0ca964bc43b49d1a868f31ece6173e2
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Host Fatty Acid Utilization by <named-content content-type="genus-species">Staphylococcus aureus</named-content> at the Infection Site

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