| Summary: | Dental caries is a chronic disease resulting from dysbiosis in the oral microbiome. Antagonism of commensal <i>Streptococcus sanguinis</i> and <i>Streptococcus gordonii</i> against cariogenic <i>Streptococcus mutans</i> is pivotal to keep the microecological balance. However, concerns are growing on antimicrobial agents in anticaries therapy, for broad spectrum antimicrobials may have a profound impact on the oral microbial community, especially on commensals. Here, we report celastrol, extracted from Traditional Chinese Medicine’s <i>Tripterygium wilfordii</i> (TW) plant, as a promising anticaries candidate. Our results revealed that celastrol showed antibacterial and antibiofilm activity against cariogenic bacteria <i>S. mutans</i> while exhibiting low cytotoxicity. By using a multispecies biofilm formed by <i>S. mutans</i> UA159, <i>S. sanguinis</i> SK36, and <i>S. gordonii</i> DL1, we observed that even at relatively low concentrations, celastrol reduced <i>S. mutans</i> proportion and thereby inhibited lactic acid production as well as water-insoluble glucan formation. We found that celastrol thwarted <i>S. mutans</i> outgrowth through the activation of pyruvate oxidase (SpxB) and H<sub>2</sub>O<sub>2</sub>-dependent antagonism between commensal oral streptococci and <i>S. mutans</i>. Our data reveal new anticaries properties of celastrol that enhance oral streptococcal antagonism, which thwarts <i>S. mutans</i> outgrowth, indicating its potential to maintain oral microbial balance for prospective anticaries therapy.
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