UC Berkeley

Streptococcus mutans is a major constituent of dental plaque and a major etiological agent of dental caries, one of the most prevalent medical conditions with an annual disease burden in the billions, including several hundred million children. Canonically, three attributes of S. mutans comprise its ability to cause dental cavities, namely, acidogenicity (acid production), acidurity (endurance of acidic conditions), and biofilm formation. Although these traits explain much of caries etiology, and their molecular underpinnings are often well-established, the complete picture is increasingly appreciated to involve specialized metabolism.In this dissertation, I discuss the discovery, biological activity, and biosynthesis of two novel specialized metabolite families originating from distinct biosynthetic gene clusters in S. mutans. I begin by introducing the reader to specialized metabolites isolated from nasal/oral microbiota in Chapter 1. I argue these specialized metabolites play key roles in microbial physiology and ecology, but that they remain an understudied facet of oral microbiology. In Chapter 2, I present the discovery of mutanoclumpin-583, a macrocyclic lipopeptide produced by a biosynthetic gene cluster (mcg) widespread in lactic acid bacteria. I further discuss the contribution of mutanoclumpin to autoaggregation and biofilm formation, phenotypes with potential clinical relevance. In Chapter 3, I discuss studies on the biosynthesis of mutanoclumpin family metabolites. In Chapter 4, I present preliminary studies on the regulatory circuit governing mutanoclumpin production and transporter activity in mutanoclumpin localization. I highlight that a complete model of mutanoclumpin biological activity requires further study on McgR, a transcriptional regulator, and the many transporters encoded in mcg. Finally, in Chapter 5, I discuss the successful design and implementation of a synthetic biology strategy to unveil the specialized metabolite product of BGC6, a hybrid NRPS/PKS gene cluster widespread in lactic acid bacteria. In summary, my studies have revealed two new specialized metabolite families produced by S. mutans clinical isolates and present avenues for additional research in the chemical ecology of S. mutans.