UC San Diego

Microorganisms interact with their surrounding environment via the production of metabolites, which they use to regulate growth, obtain nutrients, signal, and compete with other microbes. Polyketides are a diverse and bioactive class of microbially-produced specialized metabolites. Microbial polyketide synthase (PKS) genes encode the biosynthesis of polyketides, although differences in PKS biosynthetic gene cluster (BGC) structure can lead to structural diversity in polyketides ranging from small aromatic compounds to large macrolides. With advances in DNA sequencing technologies, genome mining has become a valuable method for natural product discovery. The webtool NaPDoS2 detects ketosynthase (KS) domains from genomic, metagenomic, and amplicon query data and utilizes phylogenetic conservation to classify the type of polyketide synthase in which they reside. In this thesis, I employed a range of microbiological, genomic, and bioinformatic techniques to probe for untapped polyketide biosynthetic potential across Earth’s microbiomes and the tree of life. In my second chapter, I assessed PKS diversity and distributions by classifying KS domains across 137 metagenomes using NaPDoS2. From this, biomes were found to be differentially enriched in type I KS domains, providing a roadmap for future biodiscovery strategies. Furthermore, KS phylogenies reveal sediment-specific clades that do not include biochemically characterized PKSs, highlighting the biosynthetic potential of poorly explored environments. After exploring metagenomes, I was curious how polyketide biosynthetic potential varies across the tree of life. To investigate this, I analyzed the KS diversity from over 600,000 genomes across the tree of life in chapter 3. This work illuminated that underexplored taxonomic lineages carry KS domains that differ from known polyketide biosynthetic pathways. Finally, in chapter 4, I used multi-omics (KS amplicon sequencing, metagenomics and metabolomics) to assess the biosynthetic potential in 5000-meter deep abyssal sediments. KS amplicon sequencing showed that abyssal sediments have distinct KS sequence signatures compared to nearshore sediments. Environmental metabolomes and KS amplicon communities were also linked to distinct biogeochemical regimes across abyssal sites and sediment horizons, raising the possibility that certain PKS pathways are crucial for navigating specific microenvironments. Together, my work suggests that abyssal sediments, poorly explored biomes, and understudied taxonomic lineages harbor unique opportunities for natural product discovery.