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.
Highlights
Staphylococcus aureus is the aetiological agent for a wide range of human infections, including abscesses, septicaemia, arthritis and endocarditis
After exposure of exponentially growing cells to linoleic acid there was a very large increase in RNAIII compared to control cells, and this was observed at all stages of growth when either linoleic or oleic acid were present from the time of inoculation
Transcription of hla in MRSA252 was only up-regulated in the presence of linoleic or oleic acid in the post-exponential growth phase demonstrating maintenance of its temporal expression, despite up-regulation of RNAIII at earlier phases of growth
Summary
Staphylococcus aureus is the aetiological agent for a wide range of human infections, including abscesses, septicaemia, arthritis and endocarditis. The increased prevalence of meticillin resistant(MRSA) and vancomycin insensitive-S. aureus strains, and the emergence of community-acquired MRSA make investigations into the pathogenicity of this species imperative. This focuses research into the development of novel antimicrobial agents, which requires a rigorous study of staphylococcal physiology. Long chain unsaturated free fatty acids (LC-uFFAs), typically $C16, are known to possess anti-staphylococcal activity and LC-uFFAs are important components of the innate immune system. Assay of staphylococcal abscess homogenates has revealed the presence of anti-staphylococcal activity comprising a pool of monoglycerides and free fatty acids [8,9,10]. The most abundant compound present in this active pool was identified as linoleic acid and was found at millimolar concentrations
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