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Mutanofactin promotes adhesion and biofilm formation of cariogenic Streptococcus mutans

Abstract

Cariogenic Streptococcus mutans is known as a predominant etiological agent of dental caries due to its exceptional capacity to form biofilms. From strains of S. mutans isolated from dental plaque, we discovered, in the present study, a polyketide/nonribosomal peptide biosynthetic gene cluster, muf, which directly correlates with a strong biofilm-forming capability. We then identified the muf-associated bioactive product, mutanofactin-697, which contains a new molecular scaffold, along with its biosynthetic logic. Further mode-of-action studies revealed that mutanofactin-697 binds to S. mutans cells and also extracellular DNA, increases bacterial hydrophobicity, and promotes bacterial adhesion and subsequent biofilm formation. Our findings provided an example of a microbial secondary metabolite promoting biofilm formation via a physicochemical approach, highlighting the importance of secondary metabolism in mediating critical processes related to the development of dental caries.

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Fig. 1: Biofilm formation by S. mutans isolates with diverse BGCs.
Fig. 2: Biofilm formations by wild-type S. mutans strains and mutants.
Fig. 3: Surface physicochemical properties of S. mutans strains.
Fig. 4: Biosynthesis and chemical structures of mutanofactins.
Fig. 5: Effect of compound 5 on biofilm formation and cell self-aggregation.
Fig. 6: The role of eDNA on biofilm formation and the proposed mode of action of 5.

Data availability

The authors declare that all the data supporting the findings of the present study are available within the paper, the Supplementary Information and the Extended Data, and/or from the corresponding authors upon reasonable request. The MS raw data and searching results have been deposited to the ProteomeXchange Consortium via the PRIDE with the project accession no. PXD021641. The raw RNA-sequencing data have been deposited to the National Center for Biotechnology Information’s Sequence Read Archive database with the BioProject ID PRJNA667030.

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Acknowledgements

This work was financially supported by: grants from the Chan Zuckerberg Biohub Investigator Program to W.Z.; National Key R&D Programs of China (grant nos. 2018YFA0903200: MOST19SC04 and MOST19SC06), the China Ocean Mineral Resources Research and Development Association grant (grant no. COMRRDA17SC01) and Research Grant Council of HKSAR (grant no. C6026-19-A) to P.-Y.Q.; the Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou) to W.Z. and P.-Y.Q. (grant no. SMSEGL20SC01); and the National Institutes of Health (grant no. R01 DE13239) to R.A.B. We thank J. G. Pelton (QB3, UC, Berkeley) for assistance with NMR measurements, A. T. Iavarone (QB3, UC, Berkeley) for assistance with MS experiments and D. Schichnes (CNR Biological Imaging Facility) and Z. Hu (UC, Berkeley) for assistance with microscope experiments.

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Authors

Contributions

Z.-R.L. performed the experiments. Z.-R.L. and Y.D. analyzed the NMR data. Z.-R.L. and J.S. performed the gene and proteomic analyses. Z.-R.L. and A.P. performed the contact angle measurements. L.Z. and R.A.B. assisted with S. mutans culturing and genetics. Z.-R.L. and W.Z. designed the study and wrote the manuscript, with input from R.M., R.A.B. and P.-Y.Q.

Corresponding authors

Correspondence to Pei-Yuan Qian or Wenjun Zhang.

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Extended data

Extended Data Fig. 1 S. mutans clinical isolates with diverse biosynthetic gene clusters (BGCs).

a, Organizations of seven natural product BGCs, which are harbored in 17 selected S. mutans clinical strains. The structures of SNC1-465, mutanobactin, and mutanocyclin and reutericyclin A are shown, whose biosynthesis is linked with BGC1, BGC3, and BGC4, respectively. b, Distribution of BGCs amongst 17 S. mutans strains. c, A phylogenetic tree of 17 S. mutans strains with the annotation of their corresponding BGCs.

Extended Data Fig. 2 The effect of muf on low pH resistance and surface adhesion of Smu57.

a, The effect of pH on the growth of Smu57 and its Δmuf mutant. b, Images of early stage biofilms (6-h-old) formed by Smu57 and Δmuf mutant, which were measured to evaluate the adhesion ability of these strains. c, Quantifications of early stage biofilm (6-h-old) formation by Smu57 and its six mutants in biofilm medium by crystal violet biofilm assay (OD 575). Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. Significance was assessed using one-sided Student’s t-test. a,b, Scale bars, 1 cm.

Extended Data Fig. 3 Confocal laser scanning microscopy (CLSM) images of stained biofilms.

The biofilms formed by Smu57 and its Δmuf mutant were measured by CLSM after staining with a LIVE/DEAD BacLight Bacterial Viability Kits (SYTO-9 and propidium iodide). Green fluorescence represents viable bacteria and red fluorescence represents affected bacteria. The conventional anticaries agent chlorhexidine (5 μM) was used as a positive control. The experiment was repeated two independent times with reproducible findings. Scale bar, 20 µm.

Extended Data Fig. 4 LC–HRMS extracted ion chromatogram traces of the metabolic extracts of muf+ strains.

a, A comparison of LC–HRMS extracted ion chromatogram traces of the metabolic extracts of Smu57 (upper panel) and its Δmuf mutant (bottom panel). A 1-hour elution condition was employed. b, LC–HRMS extracted ion chromatogram traces of the metabolic extract from Smu57 (upper panel), and HPLC trace of the same sample monitored at UV λ = 330 nm (bottom panel). A 30-min elution condition was employed. c, LC–HRMS extracted ion chromatogram traces of the metabolic extract of Smu50. d, LC–HRMS extracted ion chromatogram traces of the metabolic extract of Smu56. ad, EIC + = 459.23 ± 0.01, 542.21 ± 0.01, 540.23 ± 0.01, 608.22 ± 0.01, and 698.25 ± 0.01, which correspond to compounds 1, 2, 3, 4, and 5, respectively.

Extended Data Fig. 5 Conversion of purified 5 to 4.

a, A proposed mechanism for the conversion of 5 to 4, accompanying the release of l-lactic acid (6). b, LC–HRMS extracted ion chromatogram trace of the degraded 5. EIC + = 89.02 ± 0.01, 606.21 ± 0.01, and 696.24 ± 0.01, which correspond to compounds 6, 4, and 5, respectively. Negative ion mode, LC–MS measured accurate mass spectrum was recorded across the range 50–1000 m/z.

Extended Data Fig. 6 Effects of Cys on the 5 production in various culture media.

a, Measurement of 5 production of Smu57 in biofilm medium supplemented with Cys at different concentrations. LC–HRMS extracted ion chromatogram traces of the metabolic extracts of Smu57 under different culture conditions were shown. EIC + = 698.25 ± 0.01, which corresponds to 5. b,c, Screening the optimal culture condition for 5 production. (b) A comparison of the yield of 5 from brain heart infusion (BHI) medium, BHI + Phe (1 mg/mL), BHI + Cys (1 mg/mL), and BHI + Phe+Cys (1 mg/mL for both amino acids). (c) A comparison of the yield of 5 from BHI medium supplemented with Cys at different concentrations. Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. Values with different letters represent significant differences (P < 0.05) determined by one-way ANOVA with Duncan’s test.

Extended Data Fig. 7 Effects of disruption of muf genes on the production of mutanofactins.

a, Measurement of 5 production of Smu57 and its ΔmufB, ΔmufC, and ΔmufHIJ mutants in biofilm medium. LC–HRMS extracted ion chromatogram traces of the metabolic extracts of Smu57 and its three mutants were shown. EIC + = 698.25 ± 0.01, which corresponds to 5. b,c, A comparison of the LC–HRMS extracted ion chromatogram traces of the metabolic extracts of (b) Smu57 and (c) its ΔmufB mutant. Both strains were grown in BHI medium. EIC + = 459.23 ± 0.01, 542.21 ± 0.01, 540.23 ± 0.01, 608.22 ± 0.01, and 698.25 ± 0.01, which correspond to compounds 1, 2, 3, 4, and 5, respectively. d, A comparison of the relative abundances of all mutanofactins from extracts of Smu57 and its ΔmufB mutant, based on the extracted ion chromatograms. Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. Significance was assessed using one-sided Student’s t-test.

Extended Data Fig. 8 Effects of compounds 3 and 4 on biofilm-forming ability of Smu57 Δmuf.

a, Images of biofilms formed by Δmuf mutant with 3 or 4 complementation. Scale bar, 1 cm. b, Quantification of biofilm formation by crystal violet biofilm assay (OD 575). Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. Significance was assessed using one-sided Student’s t-test.

Extended Data Fig. 9 Quantification of biofilms formed by cocultures of wild-type muf strains with Smu56.

a, Crystal violet biofilm assay (OD 575) was employed for biofilm quantification. b, Images of typical biofilms formed by different co-culture samples. Scale bar, 1 cm. c, Colony-forming units (CFUs) of indicated strains grown in co-culture biofilms, which are shown in a,b, were counted. This result shows that Smu56 coexisted with all selected wild-type muf strains. Although biofilm formation is an important microbial competition factor, Smu56 formed strong biofilm via producing compound 5, which could be hijacked by its neighboring muf S. mutans strains. a,c, Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. a, Significance was assessed using one-sided Student’s t-test.

Extended Data Fig. 10 The synergistic effects of eDNA with 5 on bacterial aggregation and biofilm formation.

a, The synergistic effect of eDNA with 5 on bacterial cell aggregation. Images of cell self-aggregation with different treatments. b, Effect of the addition of eDNA (0.2 μg/mL or 2 μg/mL) on biofilm-forming ability of Smu57 Δmuf in biofilm medium with the complementation of compound 5 (2 μg/mL). Results are presented as mean ± s.d. Data are representative of n = 3 independent experiments. Significance was assessed using one-sided Student’s t-test. a,b, Scale bars, 1 cm.

Supplementary information

Supplementary Information

Supplementary Tables 1–10, Figs. 1–19, Notes 1–3 and References.

Reporting Summary

Supplementary Dataset 1

A summary of quantitative proteomic analysis.

Supplementary Dataset 2

A summary of transcriptome analysis.

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Li, ZR., Sun, J., Du, Y. et al. Mutanofactin promotes adhesion and biofilm formation of cariogenic Streptococcus mutans. Nat Chem Biol 17, 576–584 (2021). https://doi.org/10.1038/s41589-021-00745-2

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