Microbiological Research 210 (2018) 51–58

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Microbiological Research
journal homepage: www.elsevier.com/locate/micres

Quorum sensing: A less known mode of communication among fungi T

a b a,⁎
Sajad Ahmad Padder , Rajendra Prasad , Abdul Haseeb Shah
a
Department of Bioresources, University of Kashmir, Hazratbal, Srinagar 190006, J&K, India
b
Amity Institute of Integrative Sciences and Health and Amity Institute of Biotechnology, Amity University Haryana, Amity Education Valley, Gurgaon 122413, HR, India

A R T I C LE I N FO A B S T R A C T

Keywords: Quorum sensing (QS), a density-dependent signaling mechanism of microbial cells, involves an exchange and
Quorum sensing (QS) sense of low molecular weight signaling compounds called autoinducers. With the increase in population den-
Microbial communication sity, the autoinducers accumulate in the extracellular environment and once their concentration reaches a
Candida albicans threshold, many genes are either expressed or repressed. This cell density-dependent signaling mechanism en-
Quorum sensing molecules (QSMs)
ables single cells to behave as multicellular organisms and regulates different microbial behaviors like mor-
Farnesol
phogenesis, pathogenesis, competence, biofilm formation, bioluminescence, etc guided by environmental cues.
Quorum sensing inhibitors (QSIs)
Initially, QS was regarded to be a specialized system of certain bacteria. The discovery of filamentation control in
pathogenic polymorphic fungus Candida albicans by farnesol revealed the phenomenon of QS in fungi as well.
Pathogenic microorganisms primarily regulate the expression of virulence genes using QS systems. The indirect
role of QS in the emergence of multiple drug resistance (MDR) in microbial pathogens necessitates the finding of
alternative antimicrobial therapies that target QS and inhibit the same. A related phenomenon of quorum
sensing inhibition (QSI) performed by small inhibitor molecules called quorum sensing inhibitors (QSIs) has an
ability for efficient reduction of gene expression regulated by quorum sensing. In the present review, recent
advancements in the study of different fungal quorum sensing molecules (QSMs) and quorum sensing inhibitors
(QSIs) of fungal origin along with their mechanism of action and/or role/s are discussed.

1. Introduction
Quorum sensing, a mechanism of microbial communication wherein
accumulation of signaling molecules enables a cell to sense a cell
density. It regulates several ecologically and medically important traits
in microorganisms such as competence & bioluminescence, biofilm
formation, secretion of virulence factors, sporulation & antibiotic pro-
duction. Quorum sensing phenomenon which relies on the interaction
between small diffusible signal molecules with transcriptional activator
proteins, couples the gene expression with cell density (Mallick and
Bennett, 2013; Avbelj et al., 2016; Wongsuk et al., 2016). Quorum
sensing is a well-known and widespread mechanism of cell–cell com-
munication in bacteria, wherein they communicate through signaling
molecules called autoinducers, and contribute to the regulation of the
gene expression (Wongsuk et al., 2016). Initially, QS was regarded to be
a specialized system of Vibrio fischeri wherein LuxI/LuxR transcriptional
activator and autoinducer system mediate cell density-dependent con-
trol of Lux gene expression important for the production of lumines-
cence. Later some other homologous systems in other proteobacterial
species with diverse biological roles were revealed experimentally. For
example, in Agrobacterium tumefaciens, luxI/R homologs (traI/R),
controls the conjugal transfer of plasmid between bacteria (Lang and
Faure, 2014). Similarly, in Pseudomonas aeruginosa, expression of many
virulence factors is controlled by two circuits acting in parallel
(Rasamiravaka and El Jaziri, 2016; Kariminik et al., 2017). Besides
their role in signaling, quorum sensing molecules (QSMs) do perform
other activities, like, mediation of interspecies interactions within mi-
crobial populations. For example, chemotaxis in marine diatoms toward
N-acyl homoserine lactone (AHL) signals (Williams, 2007) and the
regulation of gene expression in Burkholderia cepacia by AHLs produced
by another bacterium (Lewenza et al., 2002). A number of cell density-
dependent cellular processes regulated by such factors have been re-
ported in fungal classes as well. Studies have revealed that in fungi, like
bacteria, many population-level behaviors like pathogenesis/virulence
and biofilm formation are regulated by quorum sensing (Tarkka et al.,
2009). Small signaling molecules which concentrate in the extracellular
environment, mediate QS both in fungi as well as in bacteria. The
signaling export mechanism responsible for the accumulation of these
molecules in the medium occurs via passive diffusion across the
membrane, involving efflux pumps and specific transporters (Hogan,
2006). Once a sufficient concentration of signaling molecules is
reached, it results in the activation of a cognate response regulator

⁎
Corresponding author.
E-mail address: abdulhaseeb@kashmiruniversity.ac.in (A.H. Shah).

https://doi.org/10.1016/j.micres.2018.03.007
Received 9 January 2018; Received in revised form 21 February 2018; Accepted 17 March 2018
Available online 21 March 2018
0944-5013/ © 2018 Elsevier GmbH. All rights reserved.
S.A. Padder et al.
within the local cell population, resulting in a synchronized gene ex-
pression (Hogan, 2006). Various inter as well as intraspecific commu-
nications, their diversity, nature, and mode of action of communication
has been studied widely in fungi (Hornby et al., 2001). Fifteen years
ago, a remarkable discovery of filamentation control in pathogenic
polymorphic fungus C. albicans by farnesol revealed the phenomenon of
QS in fungi. Due to the accumulation of sesquiterpene alcohol farnesol,
dense cultures of human opportunistic pathogenic fungus C. albicans
has been reported to display a reduced tendency for the yeast-to-hyphal
switch, inferring the role of farnesol in inhibiting hyphae formation
(Hornby et al., 2001; Ramage et al., 2002). In C. albicans physiology,
farnesol plays multiple roles as signaling molecule besides having det-
rimental effects on host cells and other microbes (Albuquerque and
Casadevall, 2012). Besides farnesol, another aromatic alcohol tyrosol,
which controls growth, morphogenesis and biofilm formation also acts
as a quorum sensing molecule (QSM) in C. albicans (Albuquerque and
Casadevall, 2012). Aromatic alcohols, 1-phenylethanol, and tryptophol
regulate morphogenesis during nitrogen starvation and act as QSMs in
Saccharomyces cerevisiae (Albuquerque and Casadevall, 2012). Although
QS research in fungi is still in its infancy, population density behaviors
resembling QS have been documented in several fungal species
(Albuquerque and Casadevall, 2012; Wongsuk et al., 2016). In the last
decade, research in the field of QS focused much on probing for the
mechanism that inhibits QS signaling in microbes. To attain an un-
derstanding of QS inhibition, a generalized review of its regulation
mechanism is important. This regulation of quorum sensing phenom-
enon involves the synthesis of signal molecules which are then secreted
by the synthesizing cells either by active transport or diffusion. Since
fungi co-habit different groups of organisms- plants, animals or mi-
crobes, they need to interact with all these different groups of organ-
isms. Some fungi are also extremophiles i.e., occupy extreme niches
(Kogej et al., 2006). Organisms living in close association with different
organisms have evolved different mechanisms to cohabit different types
of organisms by producing different enzymes, chemicals or metabolites.
For example, fungi interacting closely with bacteria in soil, combat
bacterial populations for space, nutrition or pathogenicity by producing
secondary metabolites (mycotoxins) and QSIs (enzymes and other
chemicals). These metabolites and other QSIs, inhibit bacterial popu-
lations around them present in their habitat (Pitt, 2000; Frisvad et al.,
2008). In the subsequent sections, we will discuss some of these aspects
of communication in fungi brought about by the phenomena of quorum
sensing, its molecular mechanism and some quorum sensing inhibitor
molecules of fungal origin.
2. Quorum sensing in fungi
The accumulation of small diffusible molecules in the extracellular
environment mediates quorum sensing in fungi. The signaling mole-
cules are not generally strain specific and a huge diversity of those
molecules has been reported in fungi. The discovery of quorum sensing
molecule (QSM) farnesol in the pathogenic fungi C. albicans was a re-
markable breakthrough of QS in eukaryotes. Existence of QS systems in
fungi have revealed that lipids (oxylipins), peptides (pheromones), al-
cohols (tyrosol, farnesol, tryptophol, and 1-phenylethanol), acet-
aldehydes, besides some volatile compounds are actively involved in
fungal QS (Fig. 1, Table 1), regulating the diverse key functions like
pathogenesis, morphogenesis, filamentation (Fig. 2) etc (Cottier and
Mühlschlegel, 2012; Albuquerque and Casadevall, 2012; Polke et al.,
2015; Hirota et al., 2016).
Many fungal signaling pathways that are the sensors in biofilm
formation and cell culture density are modulated by QS in Aspergillus,
Candida and Saccharomyces genus (Hornby et al., 2001). Quorum sen-
sing has been reported to control budding yeast-to-polarized fila-
mentous growth transition in the dimorphic opportunistic pathogenic
fungi C. albicans, wherein the yeast form develops germ tube at low cell
density but cannot do so at high cell density. It has been reported that at
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Microbiological Research 210 (2018) 51–58
a cell density lower than 106 cells/ml, filamentous forms are developed
in C. albicans, whereas at higher cell densities the fungus grows as
budding yeasts (Hornby et al., 2001). The growth transition of C. al-
bicans appears to be important for its pathogenicity (Saville et al., 2003;
Lin et al., 2015). In general, a diversity of fungi e.g., Histoplasma cap-
sulatum, C. albicans, C. krusei, C. utilis, C. zeylanoides, C. stellata, C. in-
termedia, C. solani, C. tenuis, S. cerevisiae, Cryptococcus neoformans, As-
pergillus fumigates, Aspergillus niger, Ceratocystis ulmi, Ustilago maydis,
besides many others have been documented to undergo quorum sensing
by producing one or the other quorum sensing molecule(s) (Kruppa,
2009; Albuquerque and Casadevall 2012). In fungi, a maximum number
of QSMs have been reported in C. albicans till date. Table 1 shows some
important QS molecules among different fungal species along with their
different roles.
3. Important QS molecules and their mechanism of action
Several reports of quorum sensing like phenomena have been
documented in fungi in recent years, which mysteriously involve a
morphological transition from filamentous mycelial form to yeast or
vice-versa (Sprague and Winans, 2006). Few of the commonly known
quorum sensing molecules and their role is discussed below (also see
Table 1).
3.1. α-(1,3) –glucan
The first example of an evident QS mechanism in eukaryotes is the
regulation of the switch between the filamentous and yeast forms in
parasitic fungi Histoplasma capsulatum (Kügler et al., 2000). In the soil,
H. capsulatum exists as a free-living, saprophytic filamentous fungi but
once it is inhaled by an animal, its growth habit switches to a yeast
form, which produces some specific cell wall polysaccharides α-(1,3)-
glucan, required for its virulence, in density-dependent fashion
(Sprague and Winans, 2006). α-(1,3)-glucan biosynthesis has been
found to be associated with virulence and is the special trait of H.
capsulatum yeast phase cells (Kügler et al., 2000; Rappleye et al., 2007).
α-(1,3)-glucans have been reported to be involved in yeast protection
within phagolysosomes (Rappleye et al., 2007), regulation of yeast
proliferation within host macrophage (Kügler et al., 2000) and. the
establishment of intracellular latency (Romani, 2011)
In H. capsulatum, this polysaccharide is absent in chemotype I, while
as it is present in the cell wall of chemotype II, wherein it masks the
detection of immunostimulatory β-glucans by dectin-1 (which is pat-
tern-recognition receptor) (Brown and Gordon, 2001). Therefore in
chemotype I, no such masking of β-glucans occurs and dectin-1 re-
cognizes β-glucans, which in turn enhances phagocytosis (Marcos et al.,
2016). Thus a decreased virulence of chemotype I in vitro compared to
chemotype II has been witnessed in H. capsulatum. Though in vivo,
chemotype I maintain the virulence, possibly due to the expression of
AGS1 gene, that partially, bypasses the requirement of α-(1,3)-glucan
for yeast virulence (Edwards, 2011).
3.2. Farnesol (3,7,11-trimethyl-2,6,10-dodecatriene-1-ol)
The discovery of a quorum sensing molecule (QSM) farnesol (an
acyclic sesquiterpene alcohol), in the pathogenic fungi C. albicans was a
remarkable breakthrough in studies on QS in eukaryotes. It is en-
dogenously produced by the enzymatic dephosphorylation of mevalo-
nate pathway intermediate farnesyl diphosphate at an approximate rate
of 0.12–0.133 mg/g of dry weight of cells (Hornby et al., 2001; Ramage
et al., 2002). In C. albicans, farnesol, which is continuously released into
the environment at high cell density during growth, is the best char-
acterized QSM. It generally blocks the yeast- to- filamentous transition,
but cannot inhibit the elongation of already existing hyphae (Hornby
et al., 2001; Mosel et al., 2005; Navarathna et al., 2005). At a high
density of interwoven filamentous cells in the late stages of biofilm,
S.A. Padder et al.
Fig 1. Different quorum sensing molecules (QSMs) and quorum sensing inhibitors (QSIs) produced by fungi.
farnesol inhibits germ tube formation and triggers the dissemination of
yeast phase cells to inhabit new environments (Alem et al., 2006).
Genes associated with cell wall maintenance, cell surface hydro-
philicity, drug resistance, iron transport, hyphae formation and heat
shock proteins are affected in farnesol treated biofilms (Cao et al.,
2005). In C. albicans, farnesol has been reported to obstruct hyphal
growth by inhibiting Ras-cyclic AMP (cAMP)-protein kinase A (PKA)
cascade, besides inducing catalase-encoding gene (CAT1) expression
(Shirtliff et al., 2009). Studies have also revealed the role of quorum
sensing in morphogenesis. For instance, farnesol has been found to
inhibit MAP kinase cascade via the downregulation of CPH1 and HST7
gene expression in C. albicans (Sato et al., 2004). Many morphogenesis
associated genes are also either upregulated (e.g. TUP1, HOG1) or
down-regulated (e.g. CRK1 and PDE2), and by upregulating the global
repressor TUP1, farnesol is known to inhibit hyphae formation in C.
albicans. Furthermore, farnesol represses cAMP-PKA induced hyphae
formation, which further suppresses RAS1-CDC35 pathway in the
fungus (Cao et al., 2005; Kebaara et al., 2008). In this pathway, ade-
nylate cyclase (Cdc35) is stimulated via the activation of small GTPase
Ras1. This stimulation, in turn, promotes activation of transcription
factor(s), like Efg1 via generation of a cAMP, that facilitates the yeast-
to-hypha transition (Davis-Hanna et al., 2008). It is known that hyphal
growth regulation by this pathway is chiefly important for the virulence
of C. albicans in animal models (Davis-Hanna et al., 2008). Farnesol
produced by C. albicans also affects the growth of other Candida species
including C. parapsilosis and C. tropicalis (Weber, 2010) besides S. cer-
evisiae, Aspergillus nidulans and A. fumigatus (Weber, 2010; Joo and
Jetten 2010). In A. fumigatus, the localization of proteins involved in
regulation of the cytoskeleton and cell wall integrity (CWI) pathway
like AfRho1p and AfRho3p, has been reported to be altered by farnesol
(Dichtl et al., 2010). Furthermore, farnesol has also been reported to
increase the antibiotic sensitivity of Staphylococcus aureus and induces
apoptosis of cancerous cells, inferring that farnesol act as both inter as
well as intraspecific communication molecule (Chung et al., 2010).
Besides this, farnesol also induces apoptosis in S. cerevisiae and A. ni-
dulans through disruption of the mitochondria, induction of caspases
and the production of ROS, (Semighini et al., 2006; Fairn et al., 2007).
In C. albicans, farnesol, at a concentration of 40 μM to 100 μM has also
been shown to protect it from oxidative stress caused by H2O2,
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Microbiological Research 210 (2018) 51–58
plumbagin and menadione, by up-regulating the expression of some
oxidative stress-related genes like superoxide dismutase (SOD) and
catalase (CAT) (Westwater et al., 2005; Shirtliff et al., 2009). Farnesoic
acid, an oxidized form of farnesol is less toxic at the higher con-
centration than farnesol. It acts via PHO81 and inhibits hyphal growth
(Kim et al., 2002). However, its morphological inhibitory effect is less
compared to farnesol (Yi et al., 2011).
Besides farnesol, the alcohols derived from aromatic amino acids
tryptophan (tryptophol), phenylalanine (1-phenylethanol) and tyrosine
(tyrosol) are the other known QSMs in fungi. Tryptophol and 1-phe-
nylethanol were discovered as auto-antibiotics inhibiting filamentation
in C. albicans (Kruppa, 2009), but later on, they were found to be the
QSMs in S. cerevisiae (Chen and Fink, 2006).
3.3. Tyrosol (2-[4-hydroxyphenyl] ethanol)
Another important QSM, tyrosol (2-[4-hydroxyphenyl] ethanol), is a
tyrosine derivative, and promoter of hyphal development. Tyrosol was
the second reported and described QSM to influence morphogenesis of
C. albicans (Chen, 2004). It is released into the growth medium during
fungal growth that shortens lag-time of cells to begin germination when
present under hypha-inducing conditions (Chen, 2004). Besides, studies
have revealed that the tyrosol regulation of morphogenesis in C. albi-
cans is secondary to farnesol and is therefore considered as a minor
QSM whose influence is depictive only when farnesol is either limited
or absent in the environment (Nickerson et al., 2006). Transcript pro-
filing studies have also revealed that tyrosol affects cell cycle regula-
tion, DNA replication and chromosome segregation (Chen, 2004).
3.4. Pheromones
In fungi, pheromones are the informative molecules which assist in
plasmogamy and karyogamy by helping in the exploration of the
compatible sexual partner between. For example, S. cerevisiae produces
two types of diffusible peptide pheromones viz., a-factor and α-factor.
The a-factor and α-factor are produced by a and α cells respectively.
Individual mating type is able to produce only one of the pheromone
factors, depending on the available MAT locus allele and also responds
to the opposite factor. Released, pheromones create a concentration
S.A. Padder et al. Microbiological Research 210 (2018) 51–58

Table 1
Role and structure of different fungal quorum sensing molecules.

QSM Structure Role References

Farnesol • promotes
Blocks yeast-to- filamentous transition at high cell density and
dispersal of yeast cells by inhibiting germ tube/hyphae
Navarathna et al. (2005); Piispanen et al.
(2011); Lindsay et al. (2012); Dixon and
formation in C. albicans Hall (2015)
• affects genes associated with drug resistance, cell wall
maintenance in C. albicans
Alem et al. (2006)

• Induces apoptosis in C. albicans, S. cerevisiae & A. nidulans Cao et al. (2005); Shirtliffet al. (2009)
Tyrosol • development
Stimulates hyphae production during the early stages of biofilm Alem et al. (2006)

• Promotes germ tube formation Chen (2004)

• Antifungal activity Cordeiro et al. (2015)
α-(1,3)-glucan • Involved in yeast protection within phagolysosomes Rappleye et al. (2007)
• Establishment of intracellular latency Romani (2011)
• Regulation of yeast proliferation within a host macrophage Kügler et al. (2000)

Farnesoic acid • Inhibits hyphal growth Davis-Hanna et al. (2008)

Tryptophol • Auto-antibiotics inhibiting filamentation in C. albicans Wongsuk et al. (2016)

1-Phenyl-ethanol • Auto-antibiotics inhibiting filamentation in C. albicans Murzyn et al. (2010); Wongsuk et al.
(2016)

Pheromones
1. a-factor
• Exploration of compatible sexual partner to support karyogamy
and plasmogamy between opposite mating types in S. cerevisiae
Cottier and Mühlschleg (2011)

2. α-factor

Volatile compounds • AsWhite-opaque

a morphological cue important for C. albicans filamentation Ghosh et al. (2009); Hall et al. (2010)
(CO2) • Conidation in Neurospora
switching in C. albicans Huang et al. (2009)
• and Alternaria crassiae andcrassa, Sporulation in Alternaria crassa
Capsule formation in C. neoformans
Granger et al. (1985); Bahn et al. (2005)

gradient once they start diffusing in the environment, where they are
perceived by Ste2p and Ste3p G-protein coupled receptors present on
cells. Pheromone binding brings the separation of the monomeric α-
GTPase subunit from the linked βγ dimer, activating a protein kinase
cascade with the involvement of Ste5p and ultimately phosphorylating
two MAP kinases, Fus3p and Kss1p (Cottier and Mühlschlegel, 2011).
Phosphorylated Fus3p then triggers the expression of genes via the
activation of transcription factor Ste12p inside the nucleus. Thereafter,
as a phenotypic morphological response to opposite mating pheromone,
cells develop a shmoo, which is basically a directional growth of the cell
in response to the pheromone gradient and brings the plasmogamy
between the opposite cells (Cottier and Mühlschlegel, 2011).
3.5. Volatile compounds
Besides releasing messenger molecules onto solid growth media or
into the solution, living cells also release signaling molecules into the
air leading to the exchange of information between different cells. Long
back in the 1970s, fungal volatile compounds, having an impact on
their growth have been documented. S. cerevisiae colonies release vo-
latile ammonia and form a turbid path on agar in the vicinity of another
colony (Cottier and Mühlschlegel, 2011). Volatile compounds have
been reported to induce conidia formation in Trichoderma species.
Studies have revealed that three 8 carbon compound molecules; 3-
octanone, 3-octanol and 1-octen-3-ol, are specifically produced and
induce conidiation in Trichoderma species placed in darkness (Nemcovic
et al., 2008). The most efficient compound among the three is 1- octen-
3-ol, being active at a concentration as low as 0.1 μM. Furthermore,
above 500 μM concentration, all the compounds suppress growth and
conidia formation in Trichoderma species (Chitarra et al., 2004; Chitarra
et al., 2005). Besides volatile compounds, some fungi are responsive to
CO2 concentration. For example, Vakil et al. have observed that op-
timum germination in A. niger conidiospores occurs at a CO2 con-
centration of 0.5%, which is higher than atmospheric CO2 concentra-
tion (0.033%) (Vakil et al., 1961). Besides this, some other phenotypic
characters in fungi like sporulation in A. cassiae and A. crassa, capsule
formation/mating in C. neoformans and conidia formation in Neurospora
crassa (Park and Lee, 2004; Bahn et al., 2005; Cottier and Mühlschlegel,
2011) have been attributed to the changes in environmental CO2 con-
centration. Increased atmospheric CO2 concentration in C. albicans also
triggers the yeast to hyphae morphological switch (Khan et al., 2010),
which also enhances the switching from white to opaque forms in C.
albicans as opposed to atmospheric CO2 (Huang et al., 2009). The
reason for both these phenotypes is the involvement of C. albicans
fungal CO2 sensor- adenylyl cyclase Cyr1, which generates the sec-
ondary messenger cAMP that affects C. albicans morphology (Klengel

54
S.A. Padder et al.
Fig. 2. Quorum sensing molecules and quorum sensing inhibitors; their production and role in different cell types. Signaling molecules are produced by cell type A where they can act as
QSMs while as molecules produced by same or other fungal cells act as QSIs on cell type B.
et al., 2005; Huang et al., 2009). Further, the CYR1 inactivation de-
creases the frequency of white to opaque switching and has been re-
ported to result in the loss of filamentation at elevated CO2 levels
(Klengel et al., 2005; Huang et al., 2009). The studies of Hall et al. have
validated that the K1373 mutation in Cyr1 results in loss of C. albicans
filamentation at elevated CO2 levels inferring that the amino acid is
essential for CO2 sensing in the fungus (Hall et al., 2010). This CO2
dependent regulation of morphological switching also includes Ras1
GTPase and the transcription factor Wor1. It is worth to mention that
Cry1, Ras1 and Wor1 are essential for accelerating white to opaque
switch in response to the CO2 concentration at 1%, but at a higher CO2
concentration (20%), Cry1 and Ras1 become optional. However, Wor1
retains its essentiality for the switch even at higher concentrations
(20%) (Huang et al., 2009), inferring that at higher CO2 concentration,
an alternative CO2 sensing pathway or an increased internal pH is in-
volved in the regulation of Wor1 in C. albicans.
4. QSM farnesol and fungal drug resistance
Pathogenic fungi adopt multiple mechanisms to evade the toxic
effects of antifungal drugs currently in use. Drug efflux pump and drug
target overexpression either individually or in combination decreases
the efficacy of azole drugs and is primarily responsible for antifungal
drug resistance besides other molecular mechanisms (Cannon et al.,
2009; Prasad et al., 2017). ABC transporter encoding genes like
CaCDR1, CaCDR2 and MFS transporter encoding gene CaMDR1 have
been seen to be overexpressed in the drug-resistant clinical isolates of C.
albicans. CaCDR1 and CaCDR2 use the energy released from ATP hy-
drolysis for transporting the drug out of the cell, while CaMDR1 utilizes
H+-gradient across the plasma membrane for drug extrusion (Sanglard
and Odds 2002; Prasad et al., 2016a). Among different approaches to
combat multiple drug resistance, modulating or blocking the function of
drug efflux pump is the prime strategy (Prasad et al., 2016b).
The first QSM regulating many cell density-dependent phenomena
in eukaryotes is farnesol. The QSM farnesol, which is a precursor of
sterol biosynthesis in C. albicans, blocks the biofilm development and
morphological transition in Candida species (Hogan, 2006). It is pro-
duced from farnesyl diphosphate (FPP), which is a precursor for the
biosynthesis of ergosterol and dolichols (Hornby et al., 2003; Hornby
and Nickerson, 2004; Cottier and Mühlschlegel, 2011; Polke and
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Microbiological Research 210 (2018) 51–58
Jacobsen, 2017). Farnesol has been reported to trigger apoptosis in oral
squamous carcinoma cells of humans besides interfering with the
mammalian cell calcium signaling and membrane fluidity (Scheper
et al., 2008). Farnesol is also involved in many fungus-bacterium in-
teractions and has been reported to induce apoptosis in many other
fungi (Albuquerque and Casadevall, 2012; Dixon and Hall, 2015;
Dhamgaye et al., 2016). In C. albicans, protein expression profiling
following farnesol treatment has shown accumulation of reactive
oxygen species, mitochondrial degradation, caspase activation, and
apoptosis leading to cell death (Shirtliff et al., 2009; Léger et al., 2016).
Studies have also documented the evidence regarding the specific
modulation of efflux pumps CaCdr1p and CaCdr2p belonging to ABC
superfamily by farnesol, without having any effect on MFS transporter
CaMdr1p (Sharma and Prasad, 2011). Farnesol modulates the extrusion
ABC transporter substrates fluconazole and R6G, while as no such effect
has been observed on the efflux of CaMdr1p substrates methotrexate
and nile red. Therefore, the extrusion of only ABC transporter substrates
could be reversed/modulated by quorum sensing molecule farnesol
(Sharma and Prasad, 2011).
Biofilm formation enhances the development of fluconazole re-
sistance in C. albicans in vitro and farnesol is known to inhibit yeast
growth and biofilm formation (Yu et al., 2012). In C. albicans, resistance
towards fluconazole is more in mature biofilms than in planktonic
forms (De Backer et al., 2001; Mukherjee et al., 2003; Taff et al., 2013).
Studies have shown that QS is a possible resistance mechanism in C.
albicans biofilms. Confocal microscopic studies of farnesol-treated bio-
films have shown that they are thinner than untreated biofilms, in-
ferring to the inhibition of biofilm formation by farnesol (Ramage et al.,
2002; Wongsuk et al., 2016, Xia et al., 2017). Farnesol being the pre-
cursor for ergosterols, its exogenous exposure can alter its cellular
balance. Exposure to farnesol will also affect the ergosterol biosynth-
esis/balance in the treated cells ultimately leading to change in cellular
response to ergosterol targeting antifungal drugs (azoles) (Ramage
et al., 2002). Azole antifungals target the sterol biosynthesis and change
the intracellular and extracellular farnesol levels (Hornby and
Nickerson, 2004). Broth microdilution and disk diffusion studies have
revealed an inverse relationship between fluconazole drug and farnesol
concentration used to control the growth of both C. dubliniensis and C.
albicans strain cultures (Jabra-Rizk et al., 2006). ERG genes are known to
regulate ergosterol biosynthesis and fluconazole has been reported to
S.A. Padder et al. Microbiological Research 210 (2018) 51–58

upregulate the expression of ERG3, ERG11, ERG1and ERG25 gene, which mycorrhizosphere. For example metabolic and functional diversity of
in turn induces the drug resistance (Nailis et al., 2010). Yu et al. (2012) the soil fluorescent pseudomonads is significantly modified by the
have documented the down-regulation of ergosterol biosynthesis genes symbiotic association between Laccaria bicolor S238N an ectomycor-
upon farnesol exposure of C. albicans biofilms compared to untreated rhizal fungus and Douglas fir. This suggests that a selection strategy
control cells, Thus farnesol leads to inhibition of biofilm-mediated drug towards bacterial strains that are potentially beneficial to the fungi is
resistance in C. albicans by effecting partial gene expression in ergos- exerted by ectomycorrhizal symbiotic relationship (Frey et al., 1997;
terol biosynthesis (Yu et al., 2012). Frey-Klett et al., 2005).
The study of Rasmussen et al., 2005 on some fungal species have
revealed the production of QSIs penicillic acid and patulin by Peni-
5. Fungal quorum sensing inhibitors (QSIs)
cillium radicicola and P. coprobium respectively (Table 2) (Rasmussen
et al., 2005). DNA array analysis confirmed the quorum sensing in-
A small molecule that has an ability of efficient reduction of quorum
hibition activity of Penicillium radicicola and P. coprobium suggesting
sensing regulated gene expression is called as quorum sensing inhibitor
that the regulatory proteins RhlR and LasR are targeted by penicillic
(QSI). QSIs must be stable and these compounds should be degradation
acid and patulin proteins. These proteins regulate virulence gene ex-
resistant as they have to face various metabolic assaults. QSIs also need
pression In P. aeruginosa the expression of numerous virulence genes is
to be specific in action against the target QS systems (Rasmussen and
regulated by these two proteins in a density-dependent fashion of the
Givskov, 2006; Vattem et al., 2007). The QS signaling molecule binds to
fungal species producing them. The study further revealed that the P.
its specific receptor and generates secondary signals when threshold
aeruginosa biofilms formed in presence of patulin were susceptible to
levels of the signaling molecule are attained in the system. These sec-
tobramycin, while as a significant tolerance was observed in control
ondary signals in-turn bind to various promoter elements leading to
biofilms (de Kievit et al., 2002).
change in gene expression of the target genes in response to the sig-
Furthermore, research has revealed that various quorum sensing
nalling molecules, therefore suggesting that QS signaling can be
molecules also act as QSIs (Table 2). For example, farnesol besides
stopped by three ways: (i) hampering the production of signal mole-
acting as a strong QSM of C. albicans, harbours the antimicrobial ac-
cules, (ii) enzymatic degradation of signaling molecules, (iii) and
tivity against non-albican Candida species (Weber, 2010) besides Fu-
blocking the interaction of the signaling molecule with the respective
sarium graminearum (Semighini et al., 2006), Staphylococcus epidermidis,
the receptor molecule, which thus cannot generate secondary signals to
S. aureus (Cerca et al., 2012), Paracoccidioides brasiliensis (Derengowski,
regulate gene expression. In either case, the regulation circuit is dis-
2009) and some other bacteria (Brilhante et al., 2012). Farnesol used in
rupted.
combination with rifampicin or tetracycline shows the synergistic mode
Different molecules of fungal origin have been reported to act as
of action to increase cell death and also act as an adjuvant against S.
QSIs either against different fungal species or against some other pro-
epidermidis when used in combination with some antibiotics, where it
karyotic microbes (Fig. 1; Table 2). QSIs are one of the potential sig-
affects biofilm composition (Gomes et al., 2011; Pammi et al., 2011).
naling molecules which can be used to combat bacterial diseases, for
Farnesol has been shown to affect the metabolic pathway in S. aureus
example, halogenated furanones, produced by Delisea pulchra (Aus-
besides inducing apoptosis in A. nidulans (Semighini et al., 2006;
tralian alga) have been reported to inhibit carbapenem antibiotic
Kaneko et al., 2011). Similarly, some other studies conducted in-
synthesis and the production of exoenzyme virulence factor in the
dependently have shown that increased farnesol concentration inhibits
phytopathogen Erwinia carotovora (Manefield et al., 2001). Similarly, N-
biofilm formation in C. parapsilosis and C. tropicalis by inhibiting
acyl homoserine lactones (AHLs), which are produced and sensed as the
growing cells in the newly forming biofilms (Ramage et al., 2002;
minute, diffusible signal molecules by bacteria, regulate many diverse
Laffey and Butler, 2005; Zibafar et al., 2009). Crude extracts of Tremella
biological functions like the motility of bacterial species antibiotic and
fuciformis being non-toxic in nature can also be used as QSIs, as the
virulence factor production (Winans and Bassler, 2002; Lumjiaktase
extracts have been shown to inhibit violacein (a potent antibiotic) in
et al., 2010). Increase in cell density of AHL producing bacteria results
Chromobacterium violaceum (Zhu and Sun, 2008). Auricularia auricular is
in increased concentration of AHL in the environment. On reaching the
another edible fungus, commonly known as jelly fungi, which produce
threshold levels, AHLs lead to change in gene expression of the target
several exopolysaccharides that have significant immune-modulatory
genes (Li and Nair, 2012). Inhibition of the QS signaling related to N-
properties besides antibacterial and antitumor effects (Li and Dong,
acyl homoserine lactone (AHL) produced by bacteria is frequently
2010). Many heterocyclic compounds like cysteinyldopas, dopaquinone
performed by fungi and other organisms like plants, animals and even
and leucodopachrome used in the biosynthesis of pigments (melanin,
by other bacteria. Thus different organisms employ molecular me-
melanoid, pheomelanin) in the Jelly fungi have been reported to inhibit
chanisms to block the Quorum sensing perception and quorum sensing
the AHL-regulated signaling system besides having inhibitory activity
related functions (Uroz et al., 2003; Rasmussen et al., 2005). Fungi and
on E. coli biofilm formation (Zhu et al., 2011; Li and Dong, 2010).
mycorrhizal fungi are known to interact with different bacteria in

Table 2
Role of different QSIs of fungal origin.

QSI Source Role References

Halogenated furanones Delisea pulchra Inhibit carbapenem antibiotic synthesis and the production of Manefield et al. (2001)
exoenzyme virulence factor in the phytopathogen Erwinia
carotovora
Penicillic acid Penicillium Regulate the expression of numerous virulence genes in P. de Kievit et al. (2002)
radicicola aeruginosa
Patulin P. coprobium Regulate the expression of numerous virulence genes in P. de Kievit et al. (2002)
aeruginosa
Farnesol C. albicans Antimicrobial activity against non-albican Candida species, besides Ramage et al. (2002); Semighini et al. (2006);
some other fungi and bacteria; induce apoptosis and inhibits Weber (2010); Cerca et al. (2012); Brilhante
biofilm formation et al. (2012)
Cysteinyldopas, Dopaquinone and Auricularia Inhibit the AHL-regulated signaling system by binding to the active Zhu et al. (2011)
Leucodopachrome auricular site of receptor proteins besides having inhibitory activity on E. coli
biofilm formation

56
S.A. Padder et al.
Various enzymes of fungal origin have been reported to degrade
bacterial QSMs and biofilms. Trichosporon loubieri, a basidiomycete
anamorphic fungus, produces enzyme based QSIs that degrade different
AHLs with different N-acyl side chains ranging from C4 to C10 with/
without oxo group substitution at the C3 position via the heat-sensitive
lactonase enzyme (Wong et al., 2013).
6. Conclusion
In fungi, the cell density-dependent phenomena and their char-
acterization as quorum sensing systems along with simultaneous dis-
coveries of quorum sensing molecules is a remarkable breakthrough in
understanding this group of organisms. Analysing QS as a cell density-
dependent communication displays the fungal co-evolution with the
organisms inhabiting their environment, providing insights regarding
multispecies communication. The pervasive occurrence of diverse
quorum-sensing systems strongly advocates the importance of QS in the
successful striving of microorganisms in different habitats. Therefore,
understanding the fungal communications is of prime significance. The
disruption of QS systems or QS mediated signaling of other microbial
populations by QSI generated by fungi is yet another important means
of coordination and coexistence among different microbial populations.
So far, a number of important compounds of fungal communication
have been identified, but in most of the cases, the actual molecular
mechanism/s of such communications is still a mystery. This, in turn,
necessitates the understanding of these pathways as the expression of
many fungal virulence determinants viz. biofilm formation and yeast-
to-hyphae switch in C. albicans, synthesis of mycotoxins in A. nidulans,
capsule formation in C. neoformans, or even the multiplication of these
organisms via regulation of their asexual/sexual cycle is controlled by
these molecular messengers. Even though we have some valuable in-
formation currently in hand considering the role of these fungal
quorum sensing molecules but seemingly they play important roles
when multispecies communication and coexistence is considered which
is yet to be explored. So a better knowledge of such communications is
the prime need especially to uncover many exciting new QS systems to
better understand the cellular physiology and mutual existence in
multispecies environments. These QS systems further can be important
in determining the population densities, richness, coexistence and other
unexplored phenomena in particular environments. Furthermore, these
studies will be important to develop inventive approaches aimed at less
toxic and more effective treatment strategies to curb fungal diseases or
the production of toxins by them which will have effects on growth of
other microbial species.
Funding
AHS acknowledges the funding to his laboratory in the form of
INSPIRE faculty award (DST/INSPIRE/04/2015/001575) by
Department of Science and Technology, Government of India and Early
Career Research Award (ECR/2016/000463) by Science and
Engineering Research Board, Government of India.
Acknowledgements
We wish to thank Dr. Atanu Banerjee, Jawaharlal Nehru University,
New Delhi for his help in drawing chemical structures.
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