Monounsaturated fatty acid biosynthesis is critical for streptococcal envelope homeostasis and stress tolerance

The genus <i>Streptococcus</i> contains some of the most important commensals and pathogens of the human microbiome. To obtain the fatty acids required for cell membranes, <i>Streptococcus</i> either produce fatty acids <i>de novo</i> through the fatty acid biosynthesis (<i>fab</i>) pathway or uptake host fatty acids through the fatty acid kinase (<i>fak</i>) pathway. Although both the <i>fab</i> and <i>fak</i> pathways represent potential therapeutic targets to prevent or treat infection, progress is limited because of an incomplete understanding of taxon-to-taxon variability in streptococcal lipid metabolism. Here, we examined the role of <i>de novo</i> monounsaturated fatty acid (MUFA) synthesis in physiology and virulence-associated traits in <i>Streptococcus mutans, Streptococcus pyogenes</i>, and <i>Streptococcus pneumoniae</i>, three major pathogens that cause disease at distinct body sites. In all three species, deletion of <i>fabM</i> abolished MUFA production and caused severe growth defects, decreased stress tolerance, increased antibiotic susceptibility, and defects in cell viability, morphology, and division. In <i>S. mutans</i>, loss of <i>fabM</i> also markedly reduced competence signaling and production of the mutacin IV bacteriocin. Deletion of <i>fabM</i> increased susceptibility to killing by human neutrophils in <i>S. mutans</i> and <i>S. pneumoniae</i>, but not <i>S. pyogenes</i>. Together, these findings illustrate that MUFA synthesis is broadly important for streptococcal physiology and cell membrane homeostasis, while its contribution to pathogenesis is strongly species- and context-dependent, providing leads to guide development of novel therapeutic and/or preventative strategies.