The research to be performed in the proposed study will characterize the mechanism of Candida albicans biofilm inhibition by Enterococcus faecalis. Diverse populations of bacteria and fungi inhabit the human body and can be found living in the same niches. The polymorphic yeast, Candida albicans, and the bacterial species Enterococcus faecalis are both commensal colonizers found in overlapping niches. As opportunistic pathogens these species can cause systemic infections and are often co-isolated during infection. E. faecalis produces a secreted molecule that inhibits hyphal morphogenesis, biofilm formation, and attenuates virulence of C. albicans in a Caenorhabditis elegans infection model. Characterization of the inhibitory signal is consistent with that of a small peptide that is heat stable, 3 to 10 kDa in size, with activity dependent on the Fsr two-component system, a major regulator of E. faecalis virulence. The bacteriocin EF1097 was identified as a potential inhibitor and deletion of ef1097 reduced inhibitory activity. EF1097 is regulated by the Fsr system and belongs to the Class IIIb bacteriocins, which have a non-lytic mechanism of action against other closely related gram-positive bacteria. C. albicans biofilms grown in the presence of recombinant EF1097, expressed and purified from Escherichia coli, displayed reduced hyphal morphogenesis. The proposed study will (1) determine the regulation of EF1097 activity against C. albicans hyphal morphogenesis during biofilm formation, (2) Identify the hyphal morphogenesis pathways that are repressed by E. faecalis, and (3) determine the role of surface stress response during inhibition of hyphal morphogenesis. This study is designed to define the role of EF1097 as potential agent against C. albicans biofilms. Biofilms of C. albicans are up to 1,000-fold more resistant to antifungals compared to planktonic cells, and therefore represent a significant clinical problem. The proposed study will provide functional information about a bacterial mechanism that targets hyphal morphogenesis and biofilm formation, potentially impacting the future design of novel antifungal therapeutics.
High morbidity and mortality is correlated with infections caused by the human fungal pathogen Candida albicans, which is promoted by its ability to form biofilms on abiotic and biotic surfaces. We have identified a bacterial secreted peptide that inhibits C. albicans biofilm formation. We propose to thoroughly elucidate the mechanism by which this occurs, thereby providing new avenues for the development of therapeutics targeted against C. albicans.
| Graham, Carrie E; Cruz, Melissa R; Garsin, Danielle A et al. (2017) Enterococcus faecalis bacteriocin EntV inhibits hyphal morphogenesis, biofilm formation, and virulence of Candida albicans. Proc Natl Acad Sci U S A 114:4507-4512 |
