Modulation of Staphylococcus aureus Response to Antimicrobials by the Candida albicans Quorum Sensing Molecule Farnesol

Abstract

In microbial biofilms, microorganisms utilize secreted signaling chemical molecules to coordinate their collective behavior. Farnesol is a quorum sensing molecule secreted by the fungal species and shown to play a central physiological role during fungal biofilm growth. Our pervious and studies characterized an intricate interaction between and the bacterial pathogen , as these species coexist in biofilm. In this study, we aimed to investigate the impact of farnesol on survival, biofilm formation, and response to antimicrobials. The results demonstrated that in the presence of exogenously supplemented farnesol or farnesol secreted by in biofilm, exhibited significantly enhanced tolerance to antimicrobials. By using gene expression studies, mutant strains, and chemical inhibitors, the mechanism for the enhanced tolerance was attributed to upregulation of drug efflux pumps. Importantly, we showed that sequential exposure of to farnesol generated a phenotype of high resistance to antimicrobials. Based on the presence of intracellular reactive oxygen species upon farnesol exposure, we hypothesize that antimicrobial tolerance in may be mediated by farnesol-induced oxidative stress triggering the upregulation of efflux pumps, as part of a general stress response system. Hence, in mixed biofilms, may influence the pathogenicity of through acquisition of a drug-tolerant phenotype, with important therapeutic implications. Understanding interspecies signaling in polymicrobial biofilms and the specific drug resistance responses to secreted molecules may lead to the identification of novel targets for drug development.

Unveiling the fate of adhering bacteria to antimicrobial surfaces: expression of resistance-associated genes and macrophage-mediated phagocytosis

“…Another factor that may have contributed to this higher susceptibility is associated to norA downregulation found for cells exposed to functionalized surfaces (VAN and MIX), which was kept over time. Although the expression of norA has been mainly associated with increased tolerance and efflux of a wide variety of structurally unrelated compounds (hydrophilic fluoroquinolones, benzalkonium, ethidium bromide and rhodamine) that does not include vancomycin, [48] the expression of the Nor-family efflux pumps is not fully understood and is likely influenced by several of host and environmental conditions [56,57]. Indeed, Kong et al have reported that S. aureus tolerance to vancomycin treatment was attributed to upregulation of this drug efflux pump [57].…”

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

“…More recently, 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]. However, findings also indicated that other C. albicans secreted effectors also play a central role in mediating the process, which we identified to be the secreted quorum-sensing molecule farnesol [11].…”

“…The opportunistic fungal and bacterial pathogens Candida albicans and 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]. Our previous in vitro and in vivo studies have characterized dynamic and complex interactions between these species with important clinical and therapeutic implications [7][8][9][10][11]. More recently, 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].…”

“…One of the best-characterized QS molecules is the tetraprenoid farnesol, a key derivative in the sterol biosynthesis pathway in eukaryotic cells. In C. albicans, farnesol is endogenously generated by enzymatic dephosphorylation of farnesyl diphosphate (FPP) and secreted into the environment [11,[15][16][17]. Although 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].…”

“…To overcome the deleterious effects of oxidative stress, staphylococci employ a multitude of defense strategies controlled by a complex network of global regulators. Therefore, based on our combined previous investigations including the most recent demonstrating that farnesol modulates S. aureus cells response to antimicrobials [11], in this study, we aimed to elucidate the global impact of farnesol on S. aureus on a transcriptional level. Additionally, the close structural homology of farnesol to farnesyl diphosphate (FPP), the substrate for the CrtM enzyme responsible for STXN biosynthesis [23], led us to hypothesize that farnesol could disrupt STXN production via competitive binding to CrtM.…”