Pseudomonas aeruginosa and species of the genus Candida are frequently found occupying the same ecological niches. Although they can form mixed species infections, for example in cystic fibrosis, the interactions of Pseudomonas and Candida are predominantly antagonistic. Unfolding their full pathogenic potential strictly depends on diverse and tightly regulated population behaviors such as biofilm formation, quorum sensing signaling, induced virulence factor production for P. aeruginosa and switching from a yeast to a filamentous form for C. albicans. The antagonistic interactions of both species are taking place on multiple levels of these behavioral traits, e.g. P. aeruginosa has been shown to kill only the pathogenic filamentous but not the yeast-form of C. albicans (Hogan, 2002). Conversely, C. albicans can shut down the quorum sensing of P. aeruginosa to control its pathogenicity (Cugini et al., 2007). In preliminary work, we have shown that culture supernatants of C. albicans have a distinct and extremely selective effect on metabolites of the P. aeruginosa quinolone signaling (pqs) system. Although this antagonism between Pseudomonas and Candida has been known for decades, the chemistry of these interactions is still far from being understood. We aim to explore and elucidate the metabolites responsible for mediating the antagonism of Pseudomonas and Candida and synthetically exploit these natural products (NPs) with the goal to discover lead structures with antibiotic or antivirulence properties against these pathogens.

We will assess the activity of spent culture supernatants of P. aeruginosa strains on C. albicans / C. auris and vice versa, using pure and co-cultures in different growth media to induce potential cryptic metabolites. Bioassays will include growth inhibition of different forms and stages of both microbes (yeast-form, filamentous form, planktonic form, biofilms), motility, quorum sensing, etc. Active fractions will be purified to homogeneity and the structures of the corresponding metabolites elucidated by a combination of 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. Natural product compounds will be confirmed by re-synthesis and active molecules exploited by synthetic derivatization of the privileged core structures following ADMET characterization. Advanced hits will be shared with partners for mechanism of action and exploratory formulation studies.