Exploring the role of nonribosomal peptides in vaginal communities Jelle Dillen, Tom Eilers, Sarah Ahannach, Thies Gehrmann, Stijn Wittouck, Ilke De Boeck, Sandra Condori, Dieter Vandenheuvel, Eline Oerlemans, Peter Bron, Sarah Lebeer University of Antwerp, Belgium The vagina is a unique habitat where eubiosis is typically achieved through a Lactobacillus -dominated microbiota. Lactobacillus species such as L. crispatus and L. jensenii are often accompanied by other, less abundant key taxa such as Limosilactobacillus 1 . A lack or depletion of these genera has been associated with an increased risk of acquiring and transmitting several bacterial, fungal, and viral infections such as chlamydia, candidiasis and HIV 2,3 . Several mechanisms have been suggested to be at the core of the protective actions of lactobacilli, including competitive exclusion of pathogens through adhesion to the vaginal epithelium, modulation of the host’s immune system and production of antimicrobial natural products 3 . However, the active molecules have not yet been well studied. Antimicrobial natural products encompasses bacteriocins and other ri bosomally synthesized and post- translationally modified peptides (RiPPs), polyketide synthases (PKSs) and nonribosomal peptides (NRPs). In this study, we aimed to explore the genomic and functional role of antimicrobial natural products in vaginal lactobacilli. In our Belgian citizen science project Isala (https://isala.be/en/), we have so far obtained more than 3300 vaginal samples 1 . The microbiome compositions of these samples have been profiled by 16S rRNA amplicon sequencing. A substantial portion of the samples has already been subjected to culturing, leading to more than 2000 novel vaginal isolates so far. We then mined the genomes of 73 isolates (46 and 27 from the genera Lactobacillus and Limosilactobacillus , respectively) for the presence of putative natural product biosynthetic gene clusters. This has led to the identification of 96 clusters (61 RiPP clusters, 10 terpene-like clusters, 18 NRPS clusters, 1 hybrid NRPS/Polyketide synthase and 1 beta-lactone cluster) in 51 genomes. The identification of these NRPS clusters was not expected because vaginal Lactobacillus and Limosilactobacillus species generally have a relatively small genome (<2 Mbp) in which large biosynthetic gene clusters such as the multi-modular NRPS systems have rarely been observed 4 . The hybrid NRPS/PKS cluster showed similarity to the known reutericyclin cluster found in L. reuteri strains isolated from sourdough 5 . However, the 18 NRPS clusters shared a high sequence identity and did not show similarity to a known cluster, suggesting a novel cluster and function. We hypothesize that these nonribosomal systems might play a role in directing and stabilizing the community composition to a lactobacilli-dominated community by inhibiting (opportunistic) pathogens and thereby promoting vaginal health. This role will now be explored via functional analyses. References 1. Lebeer, S., Ahannach, S., Wittouck, S. & Gehrmann, T. (2022). Citizen-science map of the vaginal microbiome. Prepr. (Version 1) available Res. Sq.. 2. Torcia, M. G. (2019). Interplay among vaginal microbiome, immune response and sexually transmitted viral infections. International Journal of Molecular Sciences, 20 . 3. Petrova, M. I., Lievens, E., Malik, S., Imholz, N. & Lebeer, S. (2015). Lactobacillus species as biomarkers and agents that can promote various aspects of vaginal health. Frontiers in Physiology, 6 . 4. Donadio, S., Monciardini, P. & Sosio, M. (2007). Polyketide synthases and nonribosomal peptide synthetases: The emerging view from bacterial genomics. Nat. Prod. Rep. 24 , 1073–1079. 5. Lin, X. B. et al. (2015). Genetic determinants of reutericyclin biosynthesis in Lactobacillus reuteri. Appl. Environ. Microbiol., 81 , 2032–2041.
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