Cariogenic Streptococcus mutans Produces Tetramic Acid Strain-Specific Antibiotics That Impair Commensal Colonization

Abstract

Streptococcus mutans is a common constituent of dental plaque and a major etiologic agent of dental caries (tooth decay). In this study, we elucidated the biosynthetic pathway encoded by muc, a hybrid polyketide synthase and nonribosomal peptide synthetase (PKS/NRPS) biosynthetic gene cluster (BGC), present in a number of globally distributed S. mutans strains. The natural products synthesized by muc included three N-acyl tetramic acid compounds (reutericyclin and two novel analogues) and an unacylated tetramic acid (mutanocyclin). Furthermore, the enzyme encoded by mucF was identified as a novel class of membrane-associated aminoacylases and was responsible for the deacylation of reutericyclin to mutanocyclin. A large number of hypothetical proteins across a broad diversity of bacteria were homologous to MucF, suggesting that this may represent a large family of unexplored acylases. Finally, S. mutans utilized the reutericyclin produced by muc to impair the growth of neighboring oral commensal bacteria. Since S. mutans must be able to out-compete these health-associated organisms to persist in the oral microbiota and cause disease, the competitive advantage conferred by muc suggests that this BGC is likely to be involved in S. mutans ecology and therefore dental plaque dysbiosis and the resulting caries pathogenesis.

Bacterial pathogens: threat or treat (a review on bioactive natural products from bacterial pathogens)

“…These bacteria have been shown to produce structurally diverse NPs with potent bioactivities. [29][30][31][32][33] The antimicrobials from Nocardia spp. and bacteriocins from Staphylococcus spp.…”

“…66,67 Several bioactive NPs have recently been isolated from S. mutans. 30,[68][69][70][71][72][73][74][75][76][77][78] Vibrionaceae includes several species that cause intestinal (diarrhoea, cholera) and extra-intestinal (septicaemia, skin infection) illnesses in both humans and aquatic animals. Among the opportunistic Vibrio pathogens, V. parahaemolyticus has been shown to produce metabolites with remarkable bioactivity.…”

“…272,274 More recently, reutericyclin (renamed reutericyclin A 38a) and analogues reutericyclin B 38b and C 38c including the unacylated tetramic acid mutanocylin 39 were produced from the muc gene cluster in S. mutans B04Sm5 isolated from the mouth of a child with severe dental caries. 30 Mutanocyclin 39 was also reported to be produced aer the unidentied BGC1 in S. mutans 35 was activated via a new heterologous expression system. 275 The chemical structures of reutericylins A-B 38ab differ from C-D 38c-d in the presence of the N-substituted a,b-unsaturated fatty acid whereas the latter have saturated acyl chains.…”

“…275 The chemical structures of reutericylins A-B 38ab differ from C-D 38c-d in the presence of the N-substituted a,b-unsaturated fatty acid whereas the latter have saturated acyl chains. 30 In solution, tetramic acids undergo keto-enol tautomerism, and the preferred tautomeric form of reutericyclin is the pyrrolidine-2,4-dione which differs from all other naturally-occurring 3-acyl-tetramic acids. 272,276 The reutericyclin BGC in S. mutans comprises 9 genes (mucA-I) that encode a hybrid modular PKS-NRPS assembly line, as well as enzymes involved in transport and regulation.…”

Mutanofactin promotes bacterial adhesion and biofilm formation of cariogenicStreptococcus mutans

“…Recently, genomic analysis of various S. mutans isolates demonstrated that these facultative anaerobes collectively harbored a plethora of biosynthetic gene clusters (BGCs) for polyketide/non-ribosomal peptide biosynthesis [14][15][16] . Some of the associated products were also reported, including mutanobactin with an inhibitory activity against the morphological transition of Candida albicans 17,18 , mutanocyclin that suppressed the infiltration of leukocytes 19 , and reutericyclin that inhibited the growth of oral commensal bacteria 20 (Fig. 1a).…”