Evaluation of Morphogenic Regulatory Activity of Farnesoic acid and Its Derivatives against Candida albicans Dimorphism

Kim, Sanghee; Kim, Eunkyung; Shin, Dong Sun; Kang, Heonjoong; Oh, Ki Bong

doi:10.1016/s0960-894x(02)00038-0

Cited by 33 publications

(30 citation statements)

References 19 publications

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“…Since two-component signaling genes are not found in humans, it is likely that the development of two-component inhibitors may be useful in the treatment of candidiasis and candidal biofilms as well as in the dissection of the QS pathway. Such studies have recently been reported (13,17). …”

mentioning

confidence: 69%

The Two-Component Signal Transduction Protein Chk1p Regulates Quorum Sensing in Candida albicans

et al. 2004

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Regulation of hyphal morphogenesis in Candida albicans can occur through quorum sensing (QS). A QS signal, farnesol, is produced during high-density growth and inhibits morphogenesis. However, the signal transduction pathway that regulates QS is unknown. Here, we show that a C. albicans mutant lacking Chk1p but not either the Sln1p or the Nik1p histidine kinase is refractory to the inhibitory effect of farnesol both in cell suspension and during the formation of a biofilm. This study is the first to demonstrate a role for a two-component signal transduction protein in QS by a eukaryotic organism.Cell density is a critical factor in the regulation of Candida albicans hyphal morphogenesis. At a density of Ͼ10 6 cells/ml, yeast cells do not shift (germinate) to hyphae or do so at low frequencies, while at a density of Ͻ10 6 cells/ml, germination occurs (3). The relationship between cell density and new gene transcription (hyphal morphogenesis) resembles quorum sensing (QS) in some bacteria (14). Recent observations indicate that a QS system operates in C. albicans and that the isoprenoid farnesol is the QS autoinducer signal (12). Cells exposed to farnesol do not germinate, even at low cell densities. However, the regulatory and signal transduction events that direct QS are unknown, not only for C. albicans but for other fungi and eukaryotes in general. In some bacteria, two-component signaling regulates QS. Since C. albicans has several two-component signal proteins that are critical to a number of processes, including cell wall biosynthesis, adaptation to stress conditions, and virulence, our rationale was that farnesol sensing could be mediated through two-component proteins. C. albicans has three hybrid-histidine kinases, two of which have orthologues in Saccharomyces cerevisiae (Sln1p) and Neurospora crassa (Nik1p) that are presumed to play a role in an osmotic stress response (1,15,19,20). The third histidine kinase, Chk1p, has some similarity to two Schizosaccharomyces pombe proteins, Mak2p and Mak3p, which are known to function as sensors for oxidative stress (2, 5). In addition to the histidine kinases, C. albicans has two response regulator proteins, Ssk1p and Skn7p, whose S. cerevisiae homologs act downstream of the Sln1p histidine kinase (11). In C. albicans, Ssk1p and Skn7p function in the adaptation of cells to oxidant stress, while Ssk1p, in addition, regulates the expression of structural cell wall proteins and negatively regulates Chk1p expression (7, 18).The C. albicans strains used for this study have been described previously (4, 6, 9, 20). Unless noted, cells were routinely cultured in YPD (1% yeast extract, 2% dextrose, 2% peptone) or YNB (0.67% yeast nitrogen base [pH 7.0], 50 mM glucose) at 30°C. To assess whether the two-component signal transduction proteins of C. albicans play a role in QS, all strains (see Table 1) were first cultured overnight at 30°C in YPD. Subsequently, the cells were washed twice and then inoculated into 10 ml of prewarmed medium 199 (pH 7.5) with or without 250 M t...

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confidence: 69%

The Two-Component Signal Transduction Protein Chk1p Regulates Quorum Sensing in Candida albicans

et al. 2004

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“…Hornby and Nickerson later confirmed that C. albicans strain 10231 did not produce farnesol (31). Kim et al found that farnesol can inhibit hyphae formation at lower concentrations than farnesoic acid but that farnesoic acid has decreased toxicity at high concentrations (39). Of the seven strains tested, three laboratory strains and four clinical isolates, all but ATCC 10231 were found to produce farnesol at concentrations between 0.10 to 0.13 mg per g dry weight (31).…”

Section: Albicans and Autoregulationmentioning

confidence: 95%

“…The mechanism by which farnesol is sensed by C. albicans is not yet known. Two structure-function studies have characterized the elements of farnesol and farnesoic acid that are important for activity (39,85). The synthesis of biologically active fluorescent analogs of farnesol was used to show that farnesol derivatives localize to the cytoplasmic and nuclear membranes (84).…”

Section: Albicans and Autoregulationmentioning

confidence: 99%

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

2006

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Extracellular autoinducing compounds in the supernatants of microbial cultures were first recognized for their roles in the induction of genetic competence in gram-positive bacteria (17,94) and in the regulation of light production in marine vibrios (60). In 1994, this form of population-level regulation in microbes was dubbed "quorum sensing" since it enabled bacterial cells to chemically measure the density of the surrounding population (18). Subsequently, many examples of cell densitydependent regulation by extracellular factors have been found in diverse microorganisms. The widespread incidence of diverse quorum-sensing systems strongly suggests that regulation in accordance with cell density is important for the success of microbes in many environments (see references 25 and 95 for reviews).Cell density-dependent regulatory networks in microorganisms generally control processes that involve cell-cell interactions, such as group motility (10, 37) and the formation of multicellular structures (67,93,95). In a wide array of environmental and medically relevant bacteria, the development, maintenance, and dispersion of multicellular, surface-associated biofilms are in part controlled by quorum-sensing regulatory pathways (for reviews, see references 67 and 93). The uptake of extracellular DNA is often regulated in accordance with cell density presumably to enhance the chances of taking up DNA from closely related strains. For some bacteria, a link between the competence and biofilm formation has been established (69, 93). Both pathogens and symbionts that live in association with plant or animal hosts often use quorum sensing to regulate factors involved in microbe-host interactions (20,86,96). Quorum-sensing regulation may allow host-associated microbes to delay detection until an effective population has formed in the appropriate niche within the host.Recently, it has become apparent that fungi, like bacteria, also use quorum regulation to affect population-level behaviors such as biofilm formation and pathogenesis. Considering the extent to which quorum-sensing regulation controls important processes in many distantly related bacterial genera, it is not surprising that cell density-dependent regulation also appears to be prevalent in diverse fungal species. Because fungal quorum sensing has been most extensively studied in Candida albicans, a dimorphic opportunistic pathogen, the majority of this review focuses on the details of quorum-sensing regulation in this fungus. A discussion of other fungi that appear to use quorum-sensing regulation and the identities of other known fungal signaling molecules are presented, and potential connections between mating in fungi and cell density-dependent regulation are explored. The review will conclude with points relating to the ecology of quorum sensing and a discussion of quorum-sensing networks as potential targets for antifungal therapies.

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“…Carvone and perillaldehyde were found to inhibit the formation of C. albicans filamentous structures (McGeady et al ., 2002). Quorum sensing molecules such as farnesoic acid and cis ‐2‐dodecenoic acid (BDSF) inhibit C. albicans hyphae formation and appear to play a key role in regulating the C. albicans morphological transition (Oh et al ., 2001; Kim et al ., 2002; Boon et al ., 2008; Deng et al ., 2010). The recently identified small molecule filastatin exhibits excellent inhibitory activity against the cell adhesion, morphogenesis and pathogenesis of C. albicans (Fazly et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

(1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition

Zhao

Huang

Sun

et al. 2018

Microbial Biotechnology

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SummaryClinical treatment of Candida albicans infections has become more difficult due to the limited development of antifungal agents and the rapid emergence of drug resistance. In this study, we demonstrate the synthesis of a series of piperazine derivatives and the evaluation of their inhibitory activity against C. albicans virulence. Thirty‐four (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives, including 25 new compounds, were synthesized and assessed for their efficacy against the physiology and pathogenesis of C. albicans. Several compounds strongly inhibited the morphological transition and virulence of C. albicans cells, although they did not influence the growth rate of the fungal pathogen. A leading novel compound, (1‐(4‐ethoxyphenyl)‐4‐(1‐biphenylol‐2‐hydroxypropyl)‐piperazine), significantly attenuated C. albicans virulence by interfering with the process of hyphal development, but it showed no cytotoxicity against human cells at a micromolar level. These findings suggest that (1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives could potentially be developed as novel therapeutic agents for the clinical treatment of C. albicans infections by interfering with morphological transition and virulence.

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Evaluation of Morphogenic Regulatory Activity of Farnesoic acid and Its Derivatives against Candida albicans Dimorphism

Cited by 33 publications

References 19 publications

The Two-Component Signal Transduction Protein Chk1p Regulates Quorum Sensing in Candida albicans

The Two-Component Signal Transduction Protein Chk1p Regulates Quorum Sensing in Candida albicans

Talking to Themselves: Autoregulation and Quorum Sensing in Fungi

(1‐aryloxy‐2‐hydroxypropyl)‐phenylpiperazine derivatives suppress Candida albicans virulence by interfering with morphological transition

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