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Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans.

ABSTRACT: Streptococcus mutans is a major pathogen causing human dental caries. As a Gram-positive bacterium with a small genome (about 2?Mb) it is considered a poor source of natural products. Due to a recent explosion in genomic data available for S. mutans strains, we were motivated to explore the natural product production potential of this organism. Bioinformatic characterization of 169 publically available genomes of S. mutans from human dental caries revealed a surprisingly rich source of natural product biosynthetic gene clusters. Anti-SMASH analysis identified one nonribosomal peptide synthetase (NRPS) gene cluster, seven polyketide synthase (PKS) gene clusters and 136 hybrid PKS/NRPS gene clusters. In addition, 211 ribosomally synthesized and post-translationally modified peptides (RiPPs) clusters and 615 bacteriocin precursors were identified by a combined analysis using BAGEL and anti-SMASH. S. mutans harbors a rich and diverse natural product genetic capacity, which underscores the importance of probing the human microbiome and revisiting species that have traditionally been overlooked as "poor" sources of natural products.

SUBMITTER: Liu L

PROVIDER: S-EPMC5116633 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans.

Liu Liwei L Hao Tingting T Xie Zhoujie Z Horsman Geoff P GP Chen Yihua Y

Scientific reports 20161121

Streptococcus mutans is a major pathogen causing human dental caries. As a Gram-positive bacterium with a small genome (about 2 Mb) it is considered a poor source of natural products. Due to a recent explosion in genomic data available for S. mutans strains, we were motivated to explore the natural product production potential of this organism. Bioinformatic characterization of 169 publically available genomes of S. mutans from human dental caries revealed a surprisingly rich source of natural p ...[more]

PMID: 27869143

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Project description:Early childhood caries (ECC) is a chronic disease affecting the oral health of children globally. This disease is multifactorial, but a primary factor is cariogenic microorganisms such as Streptococcus mutans. Biosynthetic gene clusters (BGCs) encode small molecules with diverse biological activities that influence the development of many microbial diseases, including caries. The purpose of this study was to identify BGCs in S. mutans from a high-caries risk study population using whole-genome sequencing and assess their association with ECC. Forty representative S. mutans isolates were selected for genome sequencing from a large-scale epidemiological study of oral microbiology and dental caries in children from a localized Alabama population. A total of 252 BGCs were identified using the antiSMASH BGC-mining tool. Three types of BGCs identified herein-butyrolactone-like, ladderane-like, and butyrolactone-ladderane-like hybrid (BL-BGC)-have not been reported in S. mutans. These 3 BGCs were cross-referenced against public transcriptomics data, and were found to be highly expressed in caries subjects. Furthermore, based on a polymerase chain reaction screening for core BL genes, 93% of children with BL-BGC had ECC. The role of BL-BGC was further investigated by examining cariogenic traits and strain fitness in a deletion mutant using in vitro biofilm models. Deletion of the BL-BGC significantly increased biofilm pH as compared to the parent strain, while other virulence and fitness properties remained unchanged. Intriguingly, BL-BGC containing strains produced more acid, a key cariogenic feature, and less biofilm than the model cariogenic strain S. mutans UA159, suggesting the importance of this BL-BGC in S. mutans-mediated cariogenesity. The structure of any BL-BGC derived metabolites, their functions, and mechanistic connection with acid production remain to be elucidated. Nevertheless, this study is the first to report the clinical significance of a BL-BGC in S. mutans. This study also highlights pangenomic diversity, which is likely to affect phenotype and virulence.

Project description:Streptococcus mutans is the most significant pathogenic bacterium implicated in the formation of dental caries and, both directly and indirectly, has been associated with severe conditions such as multiple sclerosis, cerebrovascular and peripheral artery disease. Polymers able to selectively bind S. mutans and/or inhibit its adhesion to oral tissue in a non-lethal manner would offer possibilities for addressing pathogenicity without selecting for populations resistant against bactericidal agents. In the present work two libraries of 2-(dimethylamino)ethyl methacrylate (pDMAEMA)-based polymers were synthesized with various proportions of either N,N,N-trimethylethanaminium cationic- or sulfobetaine zwitterionic groups. These copolymers where initially tested as potential macromolecular ligands for S. mutans NCTC 10449, whilst Escherichia coli MG1655 was used as Gram-negative control bacteria. pDMAEMA-derived materials with high proportions of zwitterionic repeating units were found to be selective for S. mutans, in both isolated and S. mutans-E. coli mixed bacterial cultures. Fully sulfobetainized pDMAEMA was subsequently found to bind/cluster preferentially Gram-positive S. mutans and S. aureus compared to Gram negative E. coli and V. harveyi. A key initial stage of S. mutans pathogenesis involves a lectin-mediated adhesion to the tooth surface, thus the range of potential macromolecular ligands was further expanded by investigating two glycopolymers bearing α-mannopyranoside and β-galactopyranoside pendant units. Results with these polymers indicated that preferential binding to either S. mutans or E. coli can be obtained by modulating the glycosylation pattern of the chosen multivalent ligands without incurring unacceptable cytotoxicity in a model gastrointestinal cell line. Overall, our results allowed to identify a structure-property relationship for the potential antimicrobial polymers investigated, and suggest that preferential binding to Gram-positive S. mutans could be achieved by fine-tuning of the recognition elements in the polymer ligands.

Dataset Information

Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans.

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Genome mining unveils widespread natural product biosynthetic capacity in human oral microbe Streptococcus mutans.

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