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The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids.

ABSTRACT: The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection nevertheless remain unclear. Here we report that S. aureus lacking T7SS components are more susceptible to host-derived antimicrobial fatty acids. Unsaturated fatty acids such as linoleic acid (LA) elicited an increased inhibition of S. aureus mutants lacking T7SS effectors EsxC, EsxA and EsxB, or the membrane-bound ATPase EssC, compared to the wild-type (WT). T7SS mutants generated in different S. aureus strain backgrounds also displayed an increased sensitivity to LA. Analysis of bacterial membrane lipid profiles revealed that the esxC mutant was less able to incorporate LA into its membrane phospholipids. Although the ability to bind labelled LA did not differ between the WT and mutant strains, LA induced more cell membrane damage in the T7SS mutants compared to the WT. Furthermore, proteomic analyses of WT and mutant cell fractions revealed that, in addition to compromising membranes, T7SS defects induce oxidative stress and hamper their response to LA challenge. Thus, our findings indicate that T7SS contribute to maintaining S. aureus membrane integrity and homeostasis when bacteria encounter antimicrobial fatty acids.

SUBMITTER: Kengmo Tchoupa A

PROVIDER: S-EPMC7481793 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids.

Kengmo Tchoupa Arnaud A Watkins Kate E KE Jones Rebekah A RA Kuroki Agnès A Alam Mohammad Tauqeer MT Perrier Sebastien S Chen Yin Y Unnikrishnan Meera M

Scientific reports 20200909 1

The Staphylococcus aureus type VII secretion system (T7SS) exports several proteins that are pivotal for bacterial virulence. The mechanisms underlying T7SS-mediated staphylococcal survival during infection nevertheless remain unclear. Here we report that S. aureus lacking T7SS components are more susceptible to host-derived antimicrobial fatty acids. Unsaturated fatty acids such as linoleic acid (LA) elicited an increased inhibition of S. aureus mutants lacking T7SS effectors EsxC, EsxA and Esx ...[more]

PMID: 32908165

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Project description:Aminoglycoside antibiotics rely on the proton motive force to enter the bacterial cell, and facultative anaerobes like Staphylococcus aureus can shift energy generation from respiration to fermentation, becoming tolerant of aminoglycosides. Following this metabolic shift, high concentrations of aminoglycosides are required to eradicate S. aureus infections, which endangers the host due to the toxicity of aminoglycosides. Membrane-disrupting molecules prevent aminoglycoside tolerance in S. aureus by facilitating passive entry of the drug through the membrane. Polyunsaturated fatty acids (PUFAs) increase membrane permeability when incorporated into S. aureus. Here, we report that the abundant host-derived PUFA arachidonic acid increases the susceptibility of S. aureus to aminoglycosides, decreasing the aminoglycoside concentration needed to kill S. aureus. We demonstrate that PUFAs and aminoglycosides synergize to kill multiple strains of S. aureus, including both methicillin-resistant and -susceptible S. aureus. We also present data showing that PUFAs and aminoglycosides effectively kill S. aureus small colony variants, strains that are particularly recalcitrant to killing by many antibiotics. We conclude that cotreatment with PUFAs, which are molecules with low host toxicity, and aminoglycosides decreases the aminoglycoside concentration necessary to kill S. aureus, lowering the toxic side effects to the host associated with prolonged aminoglycoside exposure. IMPORTANCE Staphylococcus aureus infects every niche of the human host, and these infections are the leading cause of Gram-positive sepsis. Aminoglycoside antibiotics are inexpensive, stable, and effective against many bacterial infections. However, S. aureus can shift its metabolism to become tolerant of aminoglycosides, requiring increased concentrations and/or longer courses of treatment, which can cause severe host toxicity. Here, we report that polyunsaturated fatty acids (PUFAs), which have low host toxicity, disrupt the S. aureus membrane, making the pathogen susceptible to aminoglycosides. Additionally, cotreatment with aminoglycosides is effective at killing S. aureus small colony variants, strains that are difficult to treat with antibiotics. Taken together, the data presented herein show the promise of PUFA cotreatment to increase the efficacy of aminoglycosides against S. aureus infections and decrease the risk to the human host of antibiotic-induced toxicity.

Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a threat to global health. Consequently, much effort has focused on the development of new antimicrobials that target novel aspects of S. aureus physiology. Fatty acids are required to maintain cell viability, and bacteria synthesize fatty acids using the type II fatty acid synthesis (FASII) pathway. FASII is significantly different from human fatty acid synthesis, underscoring the therapeutic potential of inhibiting this pathway. However, many Gram-positive pathogens incorporate exogenous fatty acids, bypassing FASII inhibition and leaving the clinical potential of FASII inhibitors uncertain. Importantly, the source(s) of fatty acids available to pathogens within the host environment remains unclear. Fatty acids are transported throughout the body by lipoprotein particles in the form of triglycerides and esterified cholesterol. Thus, lipoproteins, such as low-density lipoprotein (LDL), represent a potentially rich source of exogenous fatty acids for S. aureus during infection. We sought to test the ability of LDLs to serve as a fatty acid source for S. aureus and show that cells cultured in the presence of human LDLs demonstrate increased tolerance to the FASII inhibitor triclosan. Using mass spectrometry, we observed that host-derived fatty acids present in the LDLs are incorporated into the staphylococcal membrane and that tolerance to triclosan is facilitated by the fatty acid kinase A, FakA, and Geh, a triacylglycerol lipase. Finally, we demonstrate that human LDLs support the growth of S. aureus fatty acid auxotrophs. Together, these results suggest that human lipoprotein particles are a viable source of exogenous fatty acids for S. aureus during infection.IMPORTANCE Inhibition of bacterial fatty acid synthesis is a promising approach to combating infections caused by S. aureus and other human pathogens. However, S. aureus incorporates exogenous fatty acids into its phospholipid bilayer. Therefore, the clinical utility of targeting bacterial fatty acid synthesis is debated. Moreover, the fatty acid reservoir(s) exploited by S. aureus is not well understood. Human low-density lipoprotein particles represent a particularly abundant in vivo source of fatty acids and are present in tissues that S. aureus colonizes. Herein, we establish that S. aureus is capable of utilizing the fatty acids present in low-density lipoproteins to bypass both chemical and genetic inhibition of fatty acid synthesis. These findings imply that S. aureus targets LDLs as a source of fatty acids during pathogenesis.

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The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids.

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The type VII secretion system protects Staphylococcus aureus against antimicrobial host fatty acids.

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