Corynebacterial membrane vesicles disrupt cariogenic interkingdom assemblages.

Polymicrobial diseases such as periodontal disease and caries pose significant treatment challenges due to their resistance to common approaches like antibiotic therapy. These infections exhibit increased resilience, due to microbial interactions that also disrupt host immune responses. Current research focuses on virulence and disease-promoting interactions, but less is known about interactions that could inhibit or prevent disease development. Normally human-associated microbiomes maintain homeostasis, preventing pathobionts from becoming dominant. In conditions like chronic disseminated candidiasis or severe early childhood caries (s-ECC), an overgrowth of microbes such as disrupts this balance. Typically, coexists benignly within the microbial community but can become pathogenic, forming biofilms and interacting with other microbes such as cariogenic . This interaction is particularly significant in s-ECC, where it exacerbates the disease's progression and severity. Here, we present that , itself and through its extracellular membrane vesicles disrupts interkingdom assemblages between and . Mechanistically the interaction interference occurs at the genetic level with downregulated HWP1 expression, a surface protein specifically induced in the presence of promoting the interkingdom interaction. Additionally, we show that can impede s systemic virulence in the infection model. This suggests that oral corynebacteria may act as a beneficial commensal species, exerting antifungal effects within polymicrobial communities and opening new avenues for managing polymicrobial diseases.IMPORTANCEPolymicrobial diseases such as severe early childhood caries (s-ECC) lack effective treatment options. Prevention, requiring a deeper understanding of ecological processes before the onset of disease symptoms, could be a potential strategy. In this context, we investigated how relatively abundant oral biofilm species, which are associated with oral health, can interfere with the interkingdom partnership of and . This partnership is a significant driver of tooth decay in s-ECC due to synergistic activities that increase cariogenicity. Our study reveals that oral corynebacteria, through the production of extracellular membrane vesicles, can disrupt the and partnership by inhibiting fungal hyphae formation. Additionally, the fatty acid cargo within these vesicles exhibits antifungal properties, suggesting that corynebacteria play a role in shaping microbial dynamics within the oral biofilm.