Abstract
ABSTRACTMicrobial 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 H2O2 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.
Highlights
Microbial species utilize secreted-signaling chemical molecules to coordinate their collective behavior, within polymicrobial biofilms
Farnesol was shown to play a central role in C. albicans physiology, we previously demonstrated that exposure to exogenous farnesol at above threshold levels triggers a process of apoptosis in eukaryotic cells, which was preceded by the accumulation of intracellular reactive oxygen species (ROS) [18,19]
In order to more closely reflect the dynamics in a mixed biofilm where S. aureus cells are continually exposed to farnesol secreted by C. albicans over time, S. aureus cells were passaged in culture media supplemented with farnesol to generate “sensitized” cells
Summary
Microbial species utilize secreted-signaling chemical molecules to coordinate their collective behavior, within polymicrobial biofilms. The opportunistic fungal and bacterial pathogens Candida albicans and T. Staphylococcus aureus, respectively, are the most frequent combination of organisms co-isolated from various niches in the human host [1,2,3,4,5,6]. We demonstrated that in a mixed biofilm, the matrix composed of secreted fungal cell wall polysaccharides, conferred coexisting S. aureus cells with enhanced tolerance to antimicrobials [12]. Findings indicated that other C. albicans secreted effectors play a central role in mediating the process, which we identified to be the secreted quorum-sensing molecule farnesol [11]
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