Int J Stomatol ›› 2026, Vol. 53 ›› Issue (1): 98-106.doi: 10.7518/gjkq.2026204

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Research progress on the secondary metabolite Mutanobactin of Streptococcus mutans

Jianglan Xia(),Xingqun Cheng,Hongkun Wu()   

  1. State Key Laboratory of Oral Diseases & National Center for Stomatology & National Clinical Research Center for Oral Diseases & Dept. of Geriatric Dentistry, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2024-12-04 Revised:2025-04-21 Online:2026-01-01 Published:2025-12-31
  • Contact: Hongkun Wu E-mail:1421934487@qq.com;811120691@qq.com
  • Supported by:
    National Natural Science Foundation of China(82101002);Key Research and Development Program of Sichuan Province(2021YFSY0011)

Abstract:

Dental caries is a chronic infectious disease occurring in the hard tissue of teeth under the influence of bacteria. Streptococcus mutans (S. mutans) is considered the major etiological agent of dental caries in humans. Mutanobactin is one of the secondary metabolites of S. mutans. It is one of non-ribosomal peptide/polyketide hybrid products and is mainly synthesized by the mub gene located in the TnSmu2 gene island. Additionally, the major types of this product are Mutanobactin A, B, C, and D, which can be synthesized in vitro. The Mutanobactin of S. mutans plays an important role in physiological functions ranging from oxidative stress resistance and interspecies competition to immunoregulation. Moreover, its production is affected by various regulatory mechanisms in vivo, the external environment, and commensal bacteria. This work mainly reviews the synthesis, physiological role, and related regulatory mechanisms of Mutanobactin to provide a new horizon for elucidating the caries virulence of S. mutans and new methods for oral microecological regulation and management of caries.

Key words: Streptococcus mutans, secondary metabolite, Mutanobactin, dental caries, microecological balance

CLC Number: 

  • R78

TrendMD: 

Fig 1

The phylogenetic analysis of the mub gene in Streptococcus mutans UA159"

Fig 2

Schematic diagram of the transcriptional direction of the mubgene"

Tab 1

The NRPS/PKS genes in Streptococcus mutans UA159"

基因推定的功能
SMU.1334C(sfp磷酸泛酰巯基乙胺基转移酶
SMU.1335C(fabK)烯酰(酰基载体蛋白)还原酶
SMU.1336C(pksD丙二酰辅酶A转酰酶
SMU.1337Cα/β-水解酶
SMU.1338C(mefEABC转运蛋白,大环内酯通透酶
SMU.1339C(bacC<bacD>杆菌肽合成酶
SMU.1340C(bacA 2)表面活性素合成酶(杆菌肽合成酶1)
SMU.1341C(grs)短杆菌肽S合成酶2(短杆菌肽S合成酶)
SMU.1342C(bac A杆菌肽合成酶1
SMU.1343C(pksC杂合非核糖体肽合成酶/聚酮合成酶(聚酮合成酶)
SMU.1344C(fabD酰基载体蛋白S-丙二酰转移酶
SMU.1345C(ituA)类似枯草芽孢杆菌中MycA的酰基辅酶A合成酶/连接酶
SMU.1346C(bacTⅡ型硫酯酶
SMU.1347C(ymbB<ylbB>ABC转运蛋白通透酶
SMU.1348C(pasA<psaA>ATP依赖性ABC转运蛋白
SMU.1349TetR家族转录调节因子

Fig 3

Schematic diagram of the biosynthesis of Mutanobactin A"

Tab 2

Regulation of Mutanobactin biosynthesis"

调节因子推定的主要作用
FtsH降解堆积的Mutanobactin
VicR解除HLP对基因表达的抑制,促进基因表达
VicK促进合成基因表达(SMU.1334、SMU.1335、SMU.1336、SMU.1341、SMU.1342、SMU.1344)
SMU.833蛋白促进合成相关蛋白表达(SMU.1342、SMU.1340、SMU.1341)
TreR促进合成相关蛋白表达(SMU.1342、SMU.1344c、SMU.1340、SMU.1341s、SMU.1345c、SMU.1339、SMU.1336)
XIP促进合成相关基因表达(SMU.1335c-1340)
c-di-AMP促进合成相关基因表达(SMU.1334、SMU.1335c、SMU.1336、SMU.1337c)
ClpPΔclpP突变株表现出mubR表达上调,SMU.1339-SMU.1348显著下调

Fig 4

The chemical structures of Mutanobactin A, B, C, and D"

[1] Pitts NB, Mayne C. Making cavities history: a glo-bal policy consensus for achieving a dental cavity-free future[J]. JDR Clin Trans Res, 2021, 6(3): 264-267.
[2] Kassebaum NJ, Bernabé E, Dahiya M, et al. Global burden of untreated caries: a systematic review and metaregression[J]. J Dent Res, 2015, 94(5): 650-658.
[3] Kreth J, Merritt J, Shi WY, et al. Competition and coexistence between Streptococcus mutans and Streptococcus sanguinis in the dental biofilm[J]. J Bacteriol, 2005, 187(21): 7193-7203.
[4] Lemos JA, Palmer SR, Zeng L, et al. The biology of Streptococcus mutans [J]. Microbiol Spectr, 2019, 7(1): GPP3-0051-2018.
[5] Krzyściak W, Jurczak A, Kościelniak D, et al. The virulence of Streptococcus mutans and the ability to form biofilms[J]. Eur J Clin Microbiol Infect Dis, 2014, 33(4): 499-515.
[6] Mira A, Simon-Soro A, Curtis MA. Role of micro-bial communities in the pathogenesis of periodontal diseases and caries[J]. J Clin Periodontol, 2017, 44(): S23-S38.
[7] Cheng X, Xu X, Zhou X, et al. Oxidative stress response: a critical factor affecting the ecological competitiveness of Streptococcus mutans [J]. J Oral Microbiol, 2024, 16(1): 2292539.
[8] 宁佳, 胡欣, 程兴群. 变异链球菌氧化应激调控机制的研究进展[J]. 口腔疾病防治, 2023, 31(4): 295-300.
Ning J, Hu X, Cheng XQ. Research progress on oxidative stress regulatory mechanisms in Streptococcus mutans [J]. J Prev Treatment Stomatol Dis, 2023, 31(4): 295-300.
[9] Wu C, Cichewicz R, Li Y, et al. Genomic island TnSmu2 of Streptococcus mutans harbors a nonribosomal peptide synthetase-polyketide synthase gene cluster responsible for the biosynthesis of pigments involved in oxygen and H2O2 tolerance[J]. Appl Environ Microbiol, 2010, 76(17): 5815-5826.
[10] Medema MH, Blin K, Cimermancic P, et al. anti-SMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences[J]. Nuc-leic Acids Res, 2011, 39(Web Server issue): W339-W346.
[11] 谢周杰, 张昭, 刘力伟, 等. 变形链球菌中的次级代谢产物及其在口腔生物被膜中的生态功能[J]. 生物工程学报, 2017, 33(9): 1547-1554.
Xie ZJ, Zhang Z, Liu LW, et al. Secondary metabolites from Streptococcus mutans and their ecological roles in dental biofilm[J]. Chin J Biotech, 2017, 33(9): 1547-1554.
[12] 张梦碟, 程兴群, 徐欣. 变异链球菌聚酮/非核糖体肽类次级代谢产物研究进展[J]. 四川大学学报(医学版), 2023, 54(3): 685-691.
Zhang MD, Cheng XQ, Xu X. Latest findings on polyketides/non-ribosomal peptides that are secon-dary metabolites of Streptococcus mutans [J]. J Si-chuan Univ (Med Sci), 2023, 54(3): 685-691.
[13] Zvanych R, Lukenda N, Li X, et al. Systems biosynthesis of secondary metabolic pathways within the oral human microbiome member Streptococcus mutans [J]. Mol Biosyst, 2015, 11(1): 97-104.
[14] Pultar F, Hansen ME, Wolfrum S, et al. Mutanobactin D from the human microbiome: total synthesis, configurational assignment, and biological evaluation[J]. J Am Chem Soc, 2021, 143(27): 10389-10402.
[15] Li Y, Tan J, Wang Q, et al. Comparing the indivi-dual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial[J]. Fertil Steril, 2020, 113(1): 197-204.
[16] Li Y, Liu L, Zhang G, et al. Potashchelins, a suite of lipid siderophores bearing both L-threo and L-erythro beta-hydroxyaspartic acids, acquired from the potash-salt-ore-derived extremophile Halomonas sp. MG34[J]. Front Chem, 2020, 8: 197.
[17] Chattoraj P, Banerjee A, Biswas S, et al. ClpP of Streptococcus mutans differentially regulates expression of genomic islands, mutacin production, and antibiotic tolerance[J]. J Bacteriol, 2010, 192(5): 1312-1323.
[18] Waterhouse JC, Russell RRB. Dispensable genes and foreign DNA in Streptococcus mutans [J]. Microbiology, 2006, 152(Pt 6): 1777-1788.
[19] Waterhouse JC, Swan DC, Russell RR. Comparative genome hybridization of Streptococcus mutans strains[J]. Oral Microbiol Immunol, 2007, 22(2): 103-110.
[20] Konanov DN, Krivonos DV, Ilina EN, et al. BioCAT: search for biosynthetic gene clusters produ-cing nonribosomal peptides with known structure[J]. Comput Struct Biotechnol J, 2022, 20: 1218-1226.
[21] Chattoraj P, Mohapatra SS, Rao JL, et al. Regulation of transcription by SMU.1349, a TetR family regulator, in Streptococcus mutans [J]. J Bacteriol, 2011, 193(23): 6605-6613.
[22] Biswas I, Mohapatra SS. CovR alleviates transcriptional silencing by a nucleoid-associated histone-like protein in Streptococcus mutans [J]. J Bacteriol, 2012, 194(8): 2050-2061.
[23] Lukenda N. Exploring the role of nonribosomal peptides in the human microbiome through the oral commensal Streptococcus mutans, the probiotic Lactobacillus plantarum, and Crohn’s disease associa-ted Faecalibacterium prausnitzii [D]. Ontario: McMaster University, 2012.
[24] Wang X, Du L, You J, et al. Fungal biofilm inhibitors from a human oral microbiome-derived bacte-rium[J]. Org Biomol Chem, 2012, 10: 2044-2050.
[25] Wang X. Activation of fungal silent biosythetic pathways by epigenetic modification[D]. Norman: University of Oklahoma, 2011.
[26] Joyner PM, Liu J, Zhang Z, et al. Mutanobactin A from the human oral pathogen Streptococcus mutans is a cross-kingdom regulator of the yeast-mycelium transition[J]. Org Biomol Chem, 2010, 8: 5486-5489.
[27] Wang M, Xie Z, Tang S, et al. Reductase of mutanobactin synthetase triggers sequential C-C macrocyclization, C-S bond formation, and C-C bond clea-vage[J]. Org Lett, 2020, 22(3): 960-964.
[28] Wang YQ, Cao W, Merritt J, et al. Characterization of FtsH essentiality in Streptococcus mutans via genetic suppression[J]. Front Genet, 2021, 12: 659220.
[29] Senadheera DB, Cordova M, Ayala EA, et al. Regulation of bacteriocin production and cell death by the VicRK signaling system in Streptococcus mutans [J]. J Bacteriol, 2012, 194(6): 1307-1316.
[30] Rainey K, Wilson L, Barnes S, et al. Quantitative proteomics uncovers the interaction between a virulence factor and mutanobactin synthetases in Streptococcus mutans [J]. mSphere, 2019, 4(5): e0042919.
[31] Tinder EL, Faustoferri RC, Buckley AA, et al. Ana-lysis of the Streptococcus mutans proteome during acid and oxidative stress reveals modules of protein coexpression and an expanded role for the TreR transcriptional regulator[J]. mSystems, 2022, 7(2): e0127221.
[32] Wenderska IB, Latos A, Pruitt B, et al. Transcriptional profiling of the oral pathogen Streptococcus mutans in response to competence signaling peptide XIP[J]. mSystems, 2017, 2(1): e00102-e00116.
[33] Cheng X, Zheng X, Zhou X, et al. Regulation of oxidative response and extracellular polysaccharide synthesis by a diadenylate cyclase in Streptococcus mutans [J]. Environ Microbiol, 2016, 18(3): 904-922.
[34] Wen ZT, Liao S, Bitoun JP, et al. Streptococcus mutans displays altered stress responses while enhancing biofilm formation by Lactobacillus casei in mixed-species consortium[J]. Front Cell Infect Microbiol, 2017, 7: 524.
[35] Chen L, Walker AR, Burne RA, et al. Amino sugars reshape interactions between Streptococcus mutans and Streptococcus gordonii [J]. Appl Environ Microbiol, 2020, 87(1): e01459-e01420.
[36] Bonmatin JM, Laprévote O, Peypoux F. Diversity among microbial cyclic lipopeptides: iturins and surfactins. Activity-structure relationships to design new bioactive agents[J]. Comb Chem High Throughput Screen, 2003, 6(6): 541-556.
[37] Hansen ME, Yasmin SO, Wolfrum S, et al. Total synthesis of Mutanobactins A, B from the human microbiome: macrocyclization and thiazepanone assembly in a single step[J]. Angew Chem Int Ed, 2022, 61(28): e202203051.
[38] Kravina A. Total synthesis of epicolactone and synthetic studies on Mutanobactins A and C[D]. Zürich: Eidgenössische Technische Hochschule Zürich, 2018.
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