A systematically biosynthetic investigation of lactic acid bacteria reveals diverse antagonistic bacteriocins that potentially shape the human microbiome

Abstract

Background: Lactic acid bacteria (LAB) produce various bioactive secondary metabolites (SMs), which endow LAB with a protective role for the host. However, the biosynthetic potentials of LAB-derived SMs remain elusive, particularly in their diversity, abundance, and distribution in the human microbiome. Thus, it is still unknown to what extent LAB-derived SMs are involved in microbiome homeostasis.Results: Here, we systematically investigate the biosynthetic potential of LAB from 31,977 LAB genomes, identifying 130,051 BGCs of 2,849 gene cluster families (GCFs). Most of these GCFs are species-specific or even strain-specific and uncharacterized yet. Analyzing 748 human-associated metagenomes, we gain an insight into the profile of LAB BGCs, which are highly diverse and niche-specific in the human microbiome. We discover that most LAB BGCs may encode bacteriocins with pervasive antagonistic activities predicted by machine learning models, potentially playing protective roles in the human microbiome. Class II bacteriocins, one of the most abundant and diverse LAB SMs, are particularly enriched and predominant in the vaginal microbiomes. Together with experimental validation, our metagenomic and metatranscriptomic analysis show that antagonistic class II bacteriocins potentially regulate microbial communities in the vagina, thereby contributing to microbiome homeostasis. Conclusions: Our study systematically investigates LAB biosynthetic potential and their profile in the human microbiome, linking them to the antagonistic contributions to microbiome homeostasis via omics analysis. These discoveries of the diverse and prevalent antagonistic SMs are expected to stimulate the mechanism study of LAB’s protective roles for the microbiome and host, highlighting the potential of LAB and their bacteriocins as therapeutic alternatives.

The composition of Tibetan kefir grain TKG-Y and the antibacterial potential and milk fermentation ability of S. warneri KYS-164 screened from TKG-Y

“…The most widely distributed microbial defense agents are bacteriocins, which are ribosomally synthesized peptides, in most cases, with antibacterial properties. 11 The large mixed bacterial composition in kefir grains also offers great possibilities for screening different bacteriocins. However, it has not been possible to synthesize new grains without utilizing original grains according to recent research.…”

Combinatorial discovery of antibacterials via a feature-fusion based machine learning workflow

“…29 Recently, machine learning classiers, including random forest, support vector machine, and logistic regression, have been employed to predict the antibiotic activity of products from biosynthetic gene clusters, 30 which encode and govern the production of natural metabolites. 31 However, obtaining such products under standard laboratory conditions can be challenging. 32 Moreover, the exploration of the broader chemical space beyond natural products using machine learning remains a formidable task that holds the potential for discovering entirely new chemical scaffolds.…”

Exploring the roles of ribosomal peptides in prokaryote-phage interactions through deep learning-enabled metagenome mining

“…Consequently, significant efforts have been dedicated to genome mining-guided discovery of new RiPPs [19,20]. Our recent research has focused on genomics-guided discovery of RiPPs, resulting in the identification of diverse antagonistic RiPPs from complex microbiome [21,22]. By applying rule-based genome mining strategies, we have successfully revealed previously untapped post-translational modification (PTM) enzymes involved in RiPP biosynthesis [23,24].…”