Streptococcus mutans suppresses filamentous growth of Candida albicans through secreting mutanocyclin, an unacylated tetramic acid

Abstract

Fungi and bacteria often co-exist and physically or chemically interact with each other in their natural niches. This inter-kingdom species interaction is exemplified by the gram-positive bacterial pathogen Streptococcus mutans and opportunistic fungal pathogen Candida albicans , which co-exist in the human mouth. It has been demonstrated that the dynamic interaction between these two species plays a critical role in their virulence and biofilm development. In this study, we discovered that S. mutans represses filamentous development and virulence in C. albicans through secreting a secondary metabolite, mutanocyclin (a tetramic acid). Mutanocyclin functions by regulating the PKA catabolic subunit Tpk2 and its preferential binding target Sfl1. Inactivation of Tpk2 in C. albicans results in an increased sensitivity to mutanocyclin, whereas overexpression of Tpk2 leads to an increased resistance. Dysfunction of SFL1 and its downstream target genes overrides the hyphal growth defect caused by mutanocyclin. Further investigation demonstrates that three glycosylphosphatidylinositol (GPI)-anchored proteins (Spr1, Hyr4, and Iff8), associated with cell wall biogenesis and remodeling, and a set of filamentous regulators also contribute to the mutanocyclin response. We propose that both transcriptional regulation and cell wall composition contribute to mutanocyclin-mediated filamentous inhibition. This repressive effect of mutanocyclin could function as a natural regulator of filamentous development in C. albicans .

Human-associated bacteria adopt an unusual route for synthesizing 3-acetylated tetramates for environmental adaptation

“…As mentioned above, RTCs are ionophore antibiotics capable of inhibiting the growth of many Gram-positive bacteria; MUC exhibits no antibiotic activity but can inhibit leukocyte chemotaxis and relieve the immune pressure from the host [22]. It can also suppress the hyphal formation and virulence of C. albicans [28], a familiar commensal existing in many body sites, such as the human oral cavity. The analysis of the 63 strains containing muc-like BGCs strongly supported that ecological adaptation is a driving force shaping the BGCs and their products.…”

“…Some S. mutans with the muc BGC, like the strain B04Sm5, can synthesize both RTCs and MUC. RTCs are antibiotics that inhibit the growth of many Gram-positive bacteria, including the competitors of S. mutans in the oral cavity [18], while MUC acts as an immunomodulator to protect bacteria from the host's immune attack and a regulator of filamentous development in Candida albicans [28], an opportunistic fungal pathogen. The fact that S. mutans UA140, which does not produce RTCs, has a MucF-like peptidase capable of hydrolyzing RTCs to MUC implies that some bacteria can take advantage of the chemical weapons produced by bacteria harboring the muc or rtc BGC, which aroused our interests to determine those "smart" bacteria by distribution investigation of the muc-like BGCs and the mucF-like genes.…”

Roles of Streptococcus mutans-Candida albicans interaction in early childhood caries: a literature review

“…Acidic pH, low temperature and rich nutritional conditions are conducive to C. albicans into yeast form ( Lopes and Lionakis, 2022 ). Internal regulation includes signaling pathways and the phenotype conversion system called as white -opaque transition ( Huang, 2012 ; Tao et al., 2022 ). C. albicans can adhere to the tooth enamel, and initial adhesion occurs through a strong interaction between yeast cell wall-associated adhesins and the salivary pellicle ( Gunaratnam et al., 2021 ).…”

“…S. mutans affect the filamentous development of C. albicans also by secreting a secondary metabolite mutanocyclin (a tetra acid). It is well-known that the conserved camp/protein kinase A (PKA) pathway plays a central role in many life activities of C. albicans ( Tao et al., 2022 ). Mutanocyclin can metabolize the subunit TPK2 in C. albicans in a dose-dependent manner by regulating the PKA pathway to inhibit the growth of filaments, and the inactivation of TPK2 also leads to an increase in the sensitivity of C. albicans to mutanomycin.…”