Modular biosynthesis of microbiome-derived polyketides and nonribosomal peptides: insights and opportunities for Lactobacillaceae.

Lactobacillaceae are a heterogeneous group of Gram-positive bacteria that play key roles in microbiome-dense ecosystems, particularly in mucosal habitats such as the vagina and gut, as well as in fermented foods. Widely recognized for their beneficial properties and broad applicability, they are best known for producing lactic acid and other small carboxylic acids. In contrast, their capacity to produce specialized metabolites, especially nonribosomal peptides and polyketides, has remained underexplored. These compounds, traditionally studied in soil-dwelling bacteria, are often assembled by large, multi-modular enzyme complexes, and include molecules with antibiotic, immunomodulatory and anticancer activities. Recent genomic surveys revealed that, despite their smaller genomes, Lactobacillaceae harbor numerous biosynthetic gene clusters encoding these metabolites, though only a handful has been experimentally characterized to date. Interestingly, the characterized examples display unusual domain architectures, atypical biosynthetic pathways, and novel chemical transformations. This review synthesizes current knowledge on the diversity, biosynthetic pathways and functional roles of specialized metabolites in Lactobacillaceae, and highlights their largely underexplored potential as one of the most important health-associated bacterial families known to date. Revealing their chemical repertoire not only expands our understanding of microbial specialized metabolism but also defines their roles in food preservation, plant health, and in preventing and treating infections across microbiome-rich mucosal ecosystems.