Lipidomics of bacteria, and unsaturated fatty acid production in Streptcococci

A special current emphasis of research in The Baker Lab is using lipidomics to better understand the ways in which bacteria modify their cell membranes to adapt to their environment, and in some cases, cause disease. All cells, and many viruses, have membranes, which are composed of lipid bilayers. The chemical properties of most membrane lipids render them notoriously difficult to study. As a result, lipidomics is perhaps the least utilized major ‘omics discipline, and a relative deficiency exists in understanding the consequences of the lipidome in various contexts, despite certainty in its biological importance. Bacterial cells all have at least one membrane, while Gram negative organisms have two. Bacteria produce a diversity of lipids to the extent that many species can, in fact, be identified be their lipid profile alone (Abel et al., 1963).

The Lactobacillales order of bacteria contains some of the most important pathogens and commensal organisms of the human microbiota. This includes the genera Streptococcus, Enterococcus, and Lactobacillus. Previous research has shown that a diversity of Lactobacillales increase the proportion of unsaturated fatty acids in their cell membranes in response to various environmental stresses including acid stress and oxidative stress (Fozo et al., 2004).

In the case of the caries pathogen, S. mutans, this shift to a membrane containing a greater percentage of unsaturated fatty acids was required to withstand further acid or oxidative stress, and crucially, cause disease in a rat model of dental caries (Fozo & Quivey, 2004, Fozo & Quivey, 2004, Fozo et al., 2007). Our current research project on this topic seeks to address several questions and knowledge gaps raised by these observations: (1) although it is known how S. mutans and other Lactobacillales produce unsaturated fatty acids, it is not known how this system is regulated and controlled (i.e., how it is turned on when needed), (2) it is not known how the unsaturated fatty acids are protective, and (3) although a similar response appears to occur in all tested Lactobacillales, it is not known if it is protective and/or required for virulence in organisms other than S. mutans or other disease contexts. This is a particularly important question, as Lactobacillales contains other devasting pathogens such as Streptococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, and Enterococcus faecium, all responsible for significant human morbidity and mortality. The bacterial lipid biosynthesis pathway is quite different at the molecular level than its eukaryotic counterpart, therefore it presents attractive targets for the development of novel antibiotics (Radka & Rock, 2022). Indeed, one of the few novel classes of antibiotics discovered and utilized in the past 30 years, triclosan, targeted the reductase step in bacterial fatty acid biosynthesis (distinct from the steps involved in unsaturated fatty acid biosynthesis) (Radka & Rock, 2022). Beyond this specific study and application, the impact of the bacterial lipidome on bacterial physiology and pathogenesis more broadly is an understudied field, with advancements in mass spectrometry technologies opening the door to lipidomics studies with a level of resolution not possible previously. Going forward, we envision the Baker Lab being at the forefront of bacterial lipidomics research.

This project is funded in part by NIH/NIDCR R00-DE029228.