Elucidating the Mechanisms and Biological Consequences of Exogenous Fatty Acid Utilization by Staphylococcus aureus

Abstract

Staphylococcus aureus is a significant human pathogen known for its ability to cause a range of infections, from minor skin conditions to life-threatening diseases. The ability of S. aureus to utilize exogenous fatty acids (eFAs) from the host environment has emerged as a crucial factor in its pathogenesis and antibiotic resistance. This dissertation explores the mechanisms and biological consequences of eFA utilization by S. aureus by employing advanced lipidomic techniques to elucidate the underlying processes. Chapter 2 investigates the substrate specificity of S. aureus-secreted lipases, the effect of human serum albumin on eFA incorporation, and the effect of the FASII inhibitor AFN-1252 on eFA, highlighting the adaptive mechanisms that S. aureus employs to maintain membrane integrity and resist antimicrobial agents. Chapter 3 introduces a novel analytical approach integrating an online Paternó-Büchi (PB) reaction with hydrophilic interaction liquid chromatography-ion mobility-mass spectrometry (HILIC-IM-MS) to determine the position of carbon-carbon double bonds in unsaturated lipids. This technique enhances the resolution and accuracy of lipidomic analyses, and provides detailed insights into the structural modifications of lipids produced by S. aureus under different growth conditions and treatments. Chapter 4 summarizes the key findings and discusses the broader implications of eFA use in S. aureus. These results underscore the importance of lipid metabolism in bacterial adaptation and resistance, and suggest potential targets for therapeutic intervention. Overall, this dissertation contributes to a deeper understanding of the metabolic strategies employed by S. aureus to thrive in various host environments. By elucidating the mechanisms of eFA utilization and its effects on membrane dynamics, this study provides a foundation for the development of novel antimicrobial therapies aimed at disrupting bacterial lipid metabolism and mitigating the threat of antibiotic-resistant infections.