Effect of farnesol on mevalonate pathway of Staphylococcus aureus

Kaneko, Mizuho; Togashi, Naoko; Hamashima, Hajime; Hirohara, Masayoshi; Inoué, Yoshihiro

doi:10.1038/ja.2011.49

Cited by 41 publications

(24 citation statements)

References 11 publications

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“…Kaneko et al . [42] results and ours further provide more evidence that farnesol mechanism of action in S. epidermidis is related with the cell wall membrane integrity. We are currently exploring the role of farnesol in S. epidermidis cell membrane integrity as well as its impact on biofilm physiology.…”

Section: Discussionsupporting

confidence: 76%

“…While S. epidermidis biofilms have been proposed to partially detach fragments of the biofilm [6] in order to potentially colonize other regions of the host, cell detachment is not yet fully understood, however some genetic regulation might be involved [41]. Recently Kaneko et al showed that farnesol interfered with the S. aureus mevalonate pathway, which is related with cell membrane maintenance and protein anchoring, among other important cell functions [42]. S. aureus biofilm production and metabolism is similar to S. epidermidis [43].…”

Section: Resultsmentioning

confidence: 99%

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Confocal laser scanning microscopy analysis of S. epidermidis biofilms exposed to farnesol, vancomycin and rifampicin

et al. 2012

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BackgroundStaphylococcus epidermidis is the major bacterial species found in biofilm-related infections on indwelling medical devices. Microbial biofilms are communities of bacteria adhered to a surface and surrounded by an extracellular polymeric matrix. Biofilms have been associated with increased antibiotic tolerance to the immune system. This increased resistance to conventional antibiotic therapy has lead to the search for new antimicrobial therapeutical agents. Farnesol, a quorum-sensing molecule in Candida albicans, has been described as impairing growth of several different microorganisms and we have previously shown its potential as an adjuvant in antimicrobial therapy against S. epidermidis. However, its mechanism of action in S. epidermidis is not fully known. In this work we better elucidate the role of farnesol against S: epidermidis biofilms using confocal laser scanning microscopy (CLSM).Findings24 h biofilms were exposed to farnesol, vancomycin or rifampicin and were analysed by CLSM, after stained with a Live/Dead stain, a known indicator of cell viability, related with cell membrane integrity. Biofilms were also disrupted by sonication and viable and cultivable cells were quantified by colony forming units (CFU) plating. Farnesol showed a similar effect as vancomycin, both causing little reduction of cell viability but at the same time inducing significant changes in the biofilm structure. On the other hand, rifampicin showed a distinct action in S. epidermidis biofilms, by killing a significant proportion of biofilm bacteria.ConclusionsWhile farnesol is not very efficient at killing biofilm bacteria, it damages cell membrane, as determined by the live/dead staining, in a similar way as vancomycin. Furthermore, farnesol might induce biofilm detachment, as determined by the reduced biofilm biomass, which can partially explain the previous findings regarding its role as a possible chemotherapy adjuvant.

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Confocal laser scanning microscopy analysis of S. epidermidis biofilms exposed to farnesol, vancomycin and rifampicin

et al. 2012

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“…We also demonstrated that at high concentrations, farnesol triggers a process of apoptosis in C. albicans and in human oral squamous carcinoma cells, which was preceded by ROS production in both eukaryotic cells (39)(40)(41). In S. aureus, several possibilities for farnesol's mechanism of killing have been proposed, including disruption of cell membrane integrity and leakage of K ϩ ions (38,(42)(43)(44). Therefore, given its toxicity, previous studies focused primarily on exploring the potential of exogenous farnesol as an antimicrobial agent.…”

Section: Figmentioning

confidence: 78%

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

Kong

Tsui

Kucharíková

et al. 2017

Antimicrob Agents Chemother

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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.

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“…26, 28, 29 Although free nanoparticles are devoid of antibacterial activity against S. mutans , either in planktonic phase or in biofilms (Figure 4), nanoparticle-mediated delivery may facilitate farnesol incorporation into bacterial membranes due to localized release. Whether nanoparticles enhance the ability of farnesol to disrupt membrane integrity 26, 28, 29, 66, 68, 72 or increase intracellular drug accumulation 73 awaits further mechanistic investigations.…”

Section: Resultsmentioning

confidence: 99%

pH-Activated Nanoparticles for Controlled Topical Delivery of Farnesol To Disrupt Oral Biofilm Virulence

et al. 2015

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Development of effective therapies to control oral biofilms is challenging, as topically introduced agents must avoid rapid clearance from biofilm-tooth interfaces while targeting biofilm microenvironments. Additionally, exopolysaccharide matrix and acidification of biofilm microenvironments are associated with cariogenic (caries-producing) biofilm virulence. Thus, nanoparticle carriers capable of binding to hydroxyapatite (HA), saliva-coated HA (sHA), and exopolysaccharides with enhanced drug-release at acidic pH were developed. Nanoparticles are formed from diblock copolymers composed of 2-(dimethylamino)ethyl methacrylate (DMAEMA), butyl methacrylate (BMA), and 2-propylacrylic acid (PAA) (p(DMAEMA)-b-p(DMAEMA-co-BMA-co-PAA)) that self-assemble into ~21 nm cationic nanoparticles. Nanoparticles exhibit outstanding adsorption affinities (~244 L-mmol−1) to negatively-charged HA, sHA, and exopolysaccharide-coated sHA due to strong electrostatic interactions via multivalent tertiary amines of p(DMAEMA). Owing to hydrophobic cores, Nanoparticles load farnesol, a hydrophobic antibacterial drug, at ~22 wt%. Farnesol release is pH-dependent with t1/2=7 and 15 h for release at pH 4.5 and 7.2, as Nanoparticles undergo core destabilization at acidic pH, characteristic of cariogenic biofilm microenvironments. Importantly, topical applications of farnesol-loaded nanoparticles disrupted Streptococcus mutans biofilms 4-fold more effectively than free farnesol. Mechanical stability of biofilms treated with drug-loaded nanoparticles was compromised, resulting in >2-fold enhancement in biofilm removal under shear stress compared to free farnesol and controls. Farnesol-loaded nanoparticles effectively attenuated biofilm virulence in vivo using a clinically-relevant topical treatment regimen (2×/day) in a rodent dental caries disease model. Treatment with farnesol-loaded nanoparticles reduced both the number and severity of carious lesions, while free-farnesol had no effect. Nanoparticles have great potential to enhance the efficacy of antibiofilm agents through multi-targeted binding and pH-responsive drug release due to microenvironmental triggers.

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Effect of farnesol on mevalonate pathway of Staphylococcus aureus

Cited by 41 publications

References 11 publications

Confocal laser scanning microscopy analysis of S. epidermidis biofilms exposed to farnesol, vancomycin and rifampicin

Confocal laser scanning microscopy analysis of S. epidermidis biofilms exposed to farnesol, vancomycin and rifampicin

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

pH-Activated Nanoparticles for Controlled Topical Delivery of Farnesol To Disrupt Oral Biofilm Virulence

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