The Staphylococcus aureus Response to Unsaturated Long Chain Free Fatty Acids: Survival Mechanisms and Virulence Implications

Abstract

Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the σB and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids.

Cis-2-decenoic Acid Inhibits S. aureus Growth and Biofilm In Vitro: A Pilot Study

“…For enhanced local delivery of C2DA, we are currently investigating more biocompatible solvent systems in our laboratories. Some free fatty acids have been reported to have antimicrobial properties [13,14] and serve an important role in maintaining the microbial flora of the skin [29,43]. We demonstrated that C2DA inhibited bacterial growth at higher concentrations, but not at lower concentrations.…”

“…This potential biofilm-preventative characteristic could make it useful as an adjunctive therapy for infection prevention. As in reports of several other medium-and long-chain fatty acids, studies have indicated that C2DA may also have growth inhibitory or bactericidal effects [14,29]. Further, since antibiotics have been less effective against biofilmassociated bacteria [40], C2DA could improve the efficacy of antibiotics in preventing or treating biofilm-associated infections.…”

In vitro activity, extraction, separation and structure elucidation of antibiotic produced by Streptomyces anulatus NEAE-94 active against multidrug-resistant Staphylococcus aureus

“…The most potent antibacterial fatty acid in mice is 9-hexadecenoic acid, and in humans, its isomer 6-hexadecenoic acid [29]. In humans and mice, these two 16-carbon monounsaturated fatty acids block the growth of S. aureus in the skin [29][30][31]. It has been hypothesized that fatty acids act by destabilizing the lipid bilayers of the bacterial membrane and disrupting the membrane functions [32] due to a range of effects on cellular metabolism [33][34][35][36][37][38].…”

Antimicrobial lipids: Emerging effector molecules of innate host defense

“…Both, S. aureus and S. saprophyticus express a cell wall associated surface protein, SsaF and SssF, respectively, that mediates resistance to the free fatty acid linoleic acid [85,86] . Furthermore, cell wall teichoic acids of S. aureus confer resistance to fatty acids from skin sebaceous glands [87] .…”