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

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.

Automated summary

In this study, it was discovered that the bacteria Streptococcus mutans represses filamentous development and virulence in the fungus Candida albicans through secreting a secondary metabolite called mutanocyclin. The mutanocyclin functions by regulating the PKA catabolic subunit Tpk2 and its binding target Sfl1. The cell wall biogenesis and remodeling proteins, as well as filamentous regulators, also contribute to the response to mutanocyclin.