Candida albicans quorum-sensing molecule farnesol modulates staphyloxanthin production and activates the thiol-based oxidative-stress response in Staphylococcus aureus

Abstract

Microbial species utilize secreted-signaling molecules to coordinate their behavior. Our previous investigations demonstrated a key role for the Candida albicans -secreted quorum-sensing molecule farnesol in modulating Staphylococcus aureus response to antimicrobials in mixed biofilms. In this study, we aimed to provide mechanistic insights into the impact of farnesol on S. aureus within the context of inter-species interactions. To mimic biofilm dynamics, farnesol-sensitized S. aureus cells were generated via sequential farnesol exposure. The sensitized phenotype exhibited dramatic loss of the typical pigment, which we identified as staphyloxanthin, an important virulence factor synthesized by the Crt operon in S. aureus . Additionally, farnesol exposure exerted oxidative-stress as indicated by transcriptional analysis demonstrating alterations in redox-sensors and major virulence regulators. Paradoxically, the activated stress-response conferred S. aureus with enhanced tolerance to H 2 O 2 and phagocytic killing. Since expression of enzymes in the staphyloxanthin biosynthesis pathway was not impacted by farnesol, we generated a theoretical-binding model which indicated that farnesol may block staphyloxanthin biosynthesis via competitive-binding to the CrtM enzyme crucial for staphyloxanthin synthesis, due to high structural similarity to the CrtM substrate. Finally, mixed growth with C. albicans was found to similarly induce S. aureus depigmentation, but not during growth with a farnesol-deficient C. albicans strain. Collectively, the findings demonstrate that a fungal molecule acts as a redox-cycler eliciting a bacterial stress response via activation of the thiol-based redox system under the control of global regulators. Therefore, farnesol-induced transcriptional modulations of key regulatory networks in S. aureus may modulate the pathogenesis of C. albicans-S. aureus co-infections.

Oral Candidiasis: A Disease of Opportunity

“…The interaction between C. albicans and the opportunistic pathogen Staphylococcus aureus is another seemingly synergistic fungal-bacterial interaction that was well studied [34,[207][208][209][210][211]. S. aureus commonly colonizes the skin and although the oral microenvironment is a transient one for staphylococci, S. aureus is commonly co-isolated with C. albicans from cases of DS and periodontitis [212][213][214][215].…”

Fungal Quorum-Sensing Molecules: A Review of Their Antifungal Effect against Candida Biofilms

“…Recently, several authors reported that certain quorum-sensing molecules may generate oxidative stress, especially at supraphysiological concentrations, which may have an antifungal effect [ 42 , 43 , 44 , 45 ]. The majority of data concerning fungal quorum sensing molecule-related therapeutic potential derived from C. albicans experiments, and these results cannot be always directly extrapolated to non- albicans species.…”

“…C. albicans -derived farnesol has also been shown to have an effect on the response of S. aureus to antibiotics in mixed species biofilms. Farnesol exposure results in a significant decrease in staphyloxantin, which is an important virulence factor of this bacterium [ 42 ]. Černáková et al (2018) showed that 200 μM farnesol has an inhibitory effect on C. albicans growth in mixed-species biofilms with Streptococcus mutans [ 93 ].…”

Inhibition of Mixed Biofilms of Candida albicans and Methicillin-Resistant Staphylococcus aureus by Positively Charged Silver Nanoparticles and Functionalized Silicone Elastomers

“…C. albicans -secreted β-1,3-glucan was identified as the key constituent providing the bacteria with enhanced drug tolerance [ 11 ] by reducing the diffusion of the antibiotics within the biofilm. Other products by the C. albicans biofilm like extracellular DNA [ 13 ] and farnesol [ 14 ] also raise the drug resistance of S. aureus . Furthermore, C. albicans facilitates the invasion across the mucosal barriers of S. aureus , leading to systemic infection in co-colonized patients [ 9 , 15 ].…”