Review Article Antifungal Compounds against Candida Infections from Traditional Chinese Medicine

13 Pages·2017·1.3 MB·English

Hindawi
BioMed Research International
Volume 2017, Article ID 4614183, 12 pages
https://doi.org/10.1155/2017/4614183
Review Article
Candida
Antifungal Compounds against Infections from
Traditional Chinese Medicine
XinLiu,1ZhimingMa,2JingxiaoZhang,3andLongfeiYang4
1EyeCenter,TheSecondHospitalofJilinUniversity,Changchun130041,China
2DepartmentofGastrointestinalNutritionandHerniaSurgery,TheSecondHospitalofJilinUniversity,Changchun130041,China
3DepartmentofEmergency,TheSecondHospitalofJilinUniversity,Changchun130041,China
4JilinProvincialKeyLaboratoryonMolecularandChemicalGenetics,TheSecondHospitalofJilinUniversity,
Changchun130041,China
CorrespondenceshouldbeaddressedtoLongfeiYang;[email protected]
Received 25 August 2017; Revised 25 November 2017; Accepted 6 December 2017; Published 28 December 2017
AcademicEditor:NikosChorianopoulos
Copyright©2017XinLiuetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense,which
permitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
InfectionscausedbyCandidaalbicans,oftenrefractoryandwithhighmorbidityandmortality,causeaheavyburdenonthepublic
healthwhilethecurrentantifungaldrugsarelimitedandareassociatedwithtoxicityandresistance.Manyplant-derivedmolecules
includingcompoundsisolatedfromtraditionalChinesemedicine(TCM)arereportedtohaveantifungalactivitythroughdifferent
targetssuchascellmembrane,cellwall,mitochondria,andvirulencefactors.Here,wereviewtherecentprogressintheanti-Candida
compoundsfromTCM,aswellastheirantifungalmechanisms.Consideringthediversetargetsandstructures,compoundsfrom
TCMmightbeapotentiallibraryforantifungaldrugdevelopment.
1.Introduction innate and adaptive immune components (e.g., epithelial
cells, macrophages, neutrophils, dendritic cells, defensins,
One severe health threat is infections caused by fungal
andcomplement).Whenthehostsencounterlowerfunctions
pathogens, among which Candida species are the second
of immune system (resulting from HIV infection, organ
mostcommonfungalpathogennexttoCryptococcusneofor-
transplant, and cancer treatment [7]) or disequilibrium of
mans, responsible for about 400,000 life-threatening infec-
microflora due to the use of antibiotics [8], mucocuta-
tions per annum in the worldwide with a mortality as high
neous and superficial infections, such as oral thrush and
as 40% [1, 2]. Candida spp. accounted for 98% of central
vaginitis, come up. This fungal pathogen could also cause
venouscatheter-relatedfungemiasinpatientswithcancer[3].
life-threatening systematic infections such as candidemia.
Among the many Candida species, Candida albicans is the
Other predisposing factors of Candida infections include
mostcommonfungalpathogenofhumandiseases,followed
diabetesandoldage[9].Amongthenosocomialbloodstream
byCandidaglabrata,Candidaparapsilosis,Candidatropicalis,
infections, infections caused by C. albicans are the fourth
andCandidakrusei[2].
prevalent[10].
Asthemajoropportunisticfungalpathogen,C.albicans
dwells on the skin, in the oral cavity, mucosa of gut, Inpresent,thetherapeuticdrugsforCandidainfections
and urogenital tract as a symbiotic fungus under normal arelimitedtofiveclassesofcompounds:polyenes,allylamines,
conditions [4]. The host could discern the commensal and azoles, fluoropyrimidines, and echinocandins [11], and
pathogenicstateofC.albicans,renderingthisfungusunder amphotericin B, terbinafine, fluconazole, 5-fluorocytosine,
thesurveillanceofimmunesystem,andthebacterialmicrobe andcaspofunginareexamplesforthem[12].Drugresistance
of locales where C. albicans colonize also contributes to emerges due to pervasive application of antifungal drugs,
keepingthisfungusincheck[5,6].Thehostdefenseagainst such as fluconazole and voriconazole, for both prophylac-
C. albicans relies on a complicated network consisting of tic and therapeutic purposes [13]. Cellular and molecular
2 BioMedResearchInternational
mechanismsunderlyingdrugresistancemayincludereduced damagingtheplasmamembraneleadingtopermeabilization
accumulationofintracellulardrugsbecauseofincreaseddrug [19, 20]. The differential effects upon human and fungi
efflux (such as elevated mRNA levels of members of ABC cells imply that it may act on unique components of fungi
transportersuperfamily),mutationsingenesoftargetprotein cells,whichneedsfurtheridentification.Anothercompound
(resulting in elevated levels of target protein or reduced isolated from Sambucus williamsii, glochidioboside, shows
affinitytotargets),andmodificationofmetabolismpathways antifungal activity similar to that of (−)-olivil-9󸀠-O-𝛽-D-
(such as altered synthetic pathway of sterol which plays an glucopyranoside against C. albicans by forming pores on
important role in both structure and function of fungal cytoplasmicmembranewitharadiusrangefrom1.4to2.3nm
cell wall) [14]. Researches indicate extensive regulation of [21]. One of the products from the secondary metabolism
intracellular processes in response to antifungal drugs. The of Trachelospermum asiaticum, dihydrodehydrodiconiferyl
fungistatic property of some drugs such as azoles and 5- alcohol9󸀠-O-𝛽-D-glucoside,couldalsodepolarizethetrans-
flucytosine also contributes to the emergence of resistance membrane potential via forming pores with radii ranging
[10], while the formation of biofilm may contribute to and from 0.74nm to 1.4nm [22]. Changes in granularity and
elevate the resistance [15]. The paucity of antifungal drugs size revealed by the flow cytometry assays also involves
and the emergence of resistance make it a pressing mission alterations of the membrane properties such as osmolarity
todiscoverandidentifynewhitsandleadsfromsynthesized [22]. However, there are no evident causative link between
chemicals or natural products. Compared to synthesized disruptionofmembranepotentialandchangesofosmolarity
chemicals, natural products have many advantages such as andnoconclusionsaboutwhichcomesfirst,whichremainto
structuraldiversityandrelativelylowtoxicity. befurtherinvestigated.
Naturalproductsprovideapotentialsourceforantifungal Asacomponentoffungalcellmembranedifferentfrom
drugs,eitherintheirnascentformorasoriginaltemplatesfor the mammalian parallel and a critical modulator for differ-
structure-optimizing for more effective and safe derivatives entiation and pathogenicity of fungi, the glycosphingolipid
[16, 17]. Among the marketed antibiotics used clinically, glycosylceramideinthecellenvelopemaybepresentsabetter
about80%arederivedfromnaturalproducts[17].Traditional targetforantifungaltherapeutictreatments[23].
Chinese medicine is composed of mainly herbs that have Ergosterolplaysimportantrolesinregulatingthefluidity
beenusedforthousandsofyears.Recently,singlecompounds ofthecellmembraneandcelldivisionoffungalcells,while
isolated from many traditional Chinese herbs have been thestructuralandconformationaldifferencesbetweenergos-
demonstratedtohavevariouskindsofpharmacologicalactiv- terolandsterol(thecounterpartofergosterolinmammalian
ities,suchasantibacterial,antitumor,antiviral,andantifungal cells)underlietheantifungalmechanismofthepolyenessuch
activities. Considering the present lack of antifungal drugs asamphotericinB[12,24].Despitethelowbioavailabilityand
and the usefulness of traditional Chinese medicine, it may hightoxicityofergosterol-targetingdrugsinhumans[25,26],
be a promising strategy to develop antifungal agents from ergosterolstillpresentsagoodtargetforantifungaldrugsdue
traditionalChinesemedicines.Here,recentantifungalcom- totheimportanceofcellmembrane.
pounds from traditional Chinese medicines will be briefly Magnolol, one of the major pharmacologically active
reviewed. compounds from Magnolia officinalis which could be used
to ameliorate the symptoms such as anxiety, asthma, ner-
vousdisturbance,anddigestiveproblems[27],couldreduce
2.CompoundsTargetingCellMembrane
the content of ergosterol in the widely used C. albicans
SC5314 [28]. Compounds from essential oil of mint, such
The plasma membrane keeps the cytoplasm from circum-
as menthol, menthone, and carvone, suppress the growth
ambient environment. The integrity and fluidity of cell
ofC.albicansthroughdecreasingthecontentsofergosterol
membranemeansbeingimportanttothesurvivalandgrowth
in cell membrane and the hemolysis caused by them is less
offungalcells;oneimportantreasonisthatmanyenzymes,
than that induced by fluconazole [29]. The ergosterol levels
channels, and transporters of drugs lie on the cell mem-
couldalsobedecreasedbycarvacrol(isolatedfromOriganum
brane.Cellmembraneisthelocationwheremanymetabolic
dictamnusL.)andthymol,whichcouldexerttheirinfluence
processes occur and meanwhile it provides a barrier to
on the antioxidant defense system, increase the membrane
environmentalstresses.
permeability, block the efflux pumps, and thus restore the
Derived from Sambucus williamsii, a traditional herb
antifungalsusceptibility[30,31].AsidefromCandidaspecies,
broadlyusedforhundredsofyearstotreatfractures,edema,
antifungal activities of this compound against other fungi
and scratches in East Asian countries, (−)-olivil-9󸀠-O-𝛽-
suchasMonilinialaxahavebeenidentified[31–33].
D-glucopyranoside exerts its antifungal activity against C. TransporterssuchasABCtransportersoncellmembrane
albicans by depolarizing the cell membrane evidenced by couldinducetheeffluxofantifungals,thuscompromisingthe
influx of propidium iodide (PI) and elevated fluorescence effectsofdrugs.Treatmentwithmagnololcouldsignificantly
󸀠
of3,3 -dipropylthiacarbocyanineiodide(DiSC3(5),acyanine decrease the efflux of fluconazole, thus enhancing the anti-
dyeformeasuringmembranepotential)[18].Moreimportant fungaleffectsoffluconazole[28].
+
andencouragingisthatthiscompoundshowslittlehemolytic PM-H ATPase on cell membrane plays a vital role in
activityonhumanerythrocytes[18].Twoothercomponents keepingthetransmembraneelectrochemicalprotongradient
(both are lignans) from the same plant, lariciresinol [19] which is important for the obtaining of nutrients. The
+
and (+)-pinoresinol, show similar anti-Candida effects by intercellularpHhemostasismodulatedbyPM-H ATPaseis
BioMedResearchInternational 3
ofgreatphysiologicalimportance.Andtheenzymaticactivity ThesestudiesindicatethatplagiochinEmayexertitsantifun-
+
ofPM-H ATPase is positivelycorrelatedwith cell viability galactivitythroughdiversecurrentlyunknownmechanisms.
[29]. Carvone, menthol, and menthone could suppress the
+
PM-H ATPaseactivity,presumablytheprimarycauseofthe 3.2.Glucan. Thiscarbohydratepolymer,togetherwithchitin,
antifungaleffects[29].Theresultsalsoindicatedtheexistence is the structural component which holds the integrity and
of targets that could be easily touched by external drugs, physical strength of the cell wall. The production and
despitethefactthatmoreeffortsneedtobemade. assembly of glucan in C. albicans need a series of enzymes
andregulatorynetworks,whicharefungal-specificandthus
3.CompoundsTargetingCell rendersomefascinatingtargetsforantifungaltherapies[41].
WallComponents Themostfamousdrugsofthiskindareechinocandinssuch
as caspofungin and micafungin which inhibit the synthesis
Thestructuralintegrityofcellwallisvitaltothesurvivaland of 𝛽-1,3-glucan [10]. Although they are fast-acting, less
growthoffungalcells,asitprovidesashelterfromosmotic toxic,andfungicidal[10],mutationsin𝛽-1,3-glucansynthase
pressureandotherstressesinmilieu.Recentstudiesshowed thatconferresistancetocaspofunginhavealreadyemerged.
that it likely plays an important role in the colonization Recently,anovelterpeneantifungalSCY-078demonstrated
and biofilm formation of C. albicans, as proteins associated fungicidal activity against C. albicans through inhibiting
with adhesion, such as Als1, Als3, and Hwp1, are cell wall glucan synthase [42]. Sodium houttuyfonate, a derivative
proteins[34,35].Damagedcellwallleadstoosmoticfragility fromHouttuynia cordata Thunb.,mightexertitssynergistic
ofthefungalcell,disruptedmembrane,effluxofcytoplasmic effectwithfluconazolethroughinterferingwith𝛽-1,3-glucan
contents, and suppressed growth of fungi [13]. Cell wall is synthesisandtransportation[43].
lackinginmammalcells,whichmakesitapreferentialtarget
forpotentialantifungaldrugsforsafetyconsiderations.The 4.CompoundsTargetingMitochondria
cellwallofCandidaspeciesholdsglycoproteinsandabundant
carbohydrates, among which are largely glucan, mannose, The classical respiratory chains of mitochondria are cen-
and chitin [10]. In the following part of this review we will ters of energy production through oxidative phosphoryla-
discuss the plant-derived antifungal components acting on tion, and meanwhile mitochondria are the organelles that
cellwallelementsoronthesynthesisofthoseelements. produce metabolic intermediates used for amino acid and
lipid biosynthesis. Both energy supply and metabolites are
3.1. Chitin. As one of the major components comprising indispensable for the survival and growth of C. albicans, as
fungal cell wall, chitin is a long linear homopolymer of 𝛽- wellasmajorcellulareventsuchasyeast-to-hyphaltransition.
1,4-linkedN-acetylglucosamine(GlcNAc)andissynthesized Mitochondriaarealsoinvolvedinefflux-mediatedresistance
by the incorporation of GlcNAc units from the precursor of C. albicans to fluconazole [44] while in vitro resistance
󸀠
uridine 5 -diphospho-N-acetylglucosamine (UDP-GlcNAc) of C. glabrata to azoles is associated with mitochondrial
inareactioncatalyzedbychitinsynthetase(CHS)[36,37]. DNA deficiency [45]. Resistance to azole is also likely to
Despitethesmallpercentageinthecellwall,chitinplays be related with decreased generation of endogenous ROS
important roles in maintaining the mechanical strength of that are harmful to DNA, proteins, and lipids while ROS
thefungalcellwall,thuskeepingtheintegrityofthefungal aremainlygeneratedbyenzymecomplexes(ComplexIand
cellwall[38].Damagetothecellwallmaybeamelioratedby ComplexIII)inclassicalrespiratorychainasby-productsof
the elevated quantity of chitin in cell wall due to increased selective degradation of mitochondria [44]. Elevated levels
synthesisand/ordecreaseddegradationofchitin,whichmay ofintracellularROSareinvolvedintheantifungaleffectsof
increase the tolerance to antifungal drugs [38]. Since this fluconazoleandmiconazoleandROSalsoplayanimportant
material does not exist in human cells, this presents an role in intrinsic mitochondrial pathway of apoptosis in C.
attractive target for antifungal therapies [36]. The chemical albicans [46, 47]. Besides the common enzymes in classi-
structuresoftheclassicinhibitorsofCHS,namely,polyoxins cal respiratory chain in C. albicans cells, there also exist
andnikkomycins,makethemselvesbedegradedeasilyinvivo rotenone-insensitiveNAD(P)Hdehydrogenaseandalterna-
anddifficulttogothroughthecellmembrane,leadingtoalow tive terminal oxidases constituting the cyanide-insensitive
antifungalactivity[36,39].ThispromptsustofindnewCHS respiratory chain [48–50]. In addition, C. albicans and C.
inhibitors. parapsilosis have additional respiratory pathway called par-
Plagiochin E derived from liverwort Marchantia poly- allel respiratory chain [51]. The differences between fungal
morphaL.exertsitsantifungaleffectthroughinhibitingthe andmammalmitochondrialenzymesalsomakedeveloping
expressionofchitinsynthetasegene1(CHS1)andtherefore drugstargetingtheseenzymespossible[52].Thisisthecaseof
suppressing the activity of CHS and subsequent synthesis someagrichemicalssuchasboscalidandcarboxinthatinhibit
of chitin both in vivo and in situ [13]. Interestingly, the the succinate dehydrogenase in fungal cells [53]. Although
expression of CHS2 and CHS3 gene was upregulated by there are only few studies on drugs targeting specifically
this macrocyclic compound [13]. However, the same group mitochondriaofCandidaspp.,ME1111[2-(3,5-dimethyl-1H-
foundthatplagiochinEexposureofC.albicanscouldinduce pyrazol-1-yl)-5-methylphenol]didexertitsantifungaleffects
accumulation of reactive oxygen species (ROS) through upon human pathogens Trichophyton mentagrophytes and
malfunction of mitochondria, while pretreatment with L- Trichophytonrubrumthroughinhibitingsuccinatedehydro-
cysteinecouldcontributetothesurvivalofC.albicans[40]. genaseinmitochondriawithhighselectivity(theIC50values
4 BioMedResearchInternational
forhumancellsaremorethanthirtytimeshigherthanthat Shikonin, the major active compound isolated from
for fungal cells) [53]. In a word, mitochondria might be a Lithospermum erythrorhizon, could induce the endoge-
promisingtargetforantifungaltherapies. nousROSproduction,reducethemitochondrialmembrane
As an important constituent of many herbs of Berberi- potential, and alter mitochondrial aerobic aspiration [74].
daceae family such as Berberis vulgaris, berberine exerts its In human gastric cancer cells and TT medullary thyroid
antifungalactionbyinductionofmitochondrialdysfunction carcinomacells,shikonincouldalsoinduceROSproduction
and increased ROS generation, and its effects are in syn- and mitochondria-mediated apoptosis [75, 76]. The almost
ergy with fluconazole, even in fluconazole-resistant clinical same cytotoxicity for fungal cells and mammalian cells
isolates [54–56]. Moreover, berberine treatment could also makes shikonin a less attractive candidate for antifungal
culminate in disruption of cell wall integrity in C. albicans development.
[57] and inhibit the overexpression of drug resistance gene Curcumin,theyellowpigmentisolatedfromtheturmeric
CDR1 induced by fluphenazine [58]. Although berberine (the rhizome of the plant Curcuma longa Linn) could also
could induce apoptosis in many human cells such as HL- be used as an adjunct drug to treat pathogenic microor-
60 leukemia cells and thyroid carcinoma cells [59, 60], ganisms such as Helicobacter pylori, methicillin-resistant
berberinecouldrecoverthemitochondrialfunctioninduced Staphylococcus aureus (MRSA), and Trypanosoma cruzi.
by high-fat feeding in a rat model and could decrease the Antifungal activities against various kinds of fungi such as
triglyceride accumulation in the liver in mice [61, 62]. It Candida species, Cryptococcus neoformans, Aspergillus spp.,
alsomarkedlydecreasedtheROSgenerationinmitochondria and Sporothrix schenckii have also been demonstrated by
[62]. This makes berberine a good candidate for antifungal this compound [77, 78]. Curcumin could increase ROS
developmentalthoughtherearemuchmoretobedone. production and apoptosis in C. albicans cells, either alone
(+)-Medioresinolfromtheanti-inflammatory,analgesic, or in synergy with antifungal drugs such as azoles and
and diuretic herbal plant Sambucus williamsii, imposed on polyenes [78, 79]. In mammalian cells, curcumin could
C. albicans, could induce generation of ROS and cell cycle protect mitochondria from damage and increase the bio-
arrestandfinallyapoptosis[47].Although(+)-medioresinol genesisofmitochondria,althoughapoptosis-inducingeffects
could inhibit in vitro the proliferation of mammalian cells of curcumin have also been reported in cancer cells [80,
suchasA549,SK-MEL-2,SK-OV-3,andHCT-15cellsathigh 81]. Most importantly, this compound could be safe with a
concentrations,theIC50valuesforthesecelllinesweremuch maximumtolerancedoseof12,000mg/dayinPhaseIclinical
higherthantheMICvalueagainstC.albicanscells[47,63]. trials[82],whichpresentanadvantageoverotherantifungal
In a cohort study in Sweden, (+)-medioresinol in food did compounds.However,thepoororalbioavailabilityandpoor
notclearlyreducetheriskofesophagealandgastriccancers, solubility in aqueous solutions impede its use and promote
but at least this compound in diet did not show bad effects thedevelopmentofmethodsfordeliveringcurcumintofight
[64,65].Thesafeprofileofthisligninmakesitmoreinspiring Candidainfections[83].
although there is no report on its effects on mammalian Silibinin,themostfamousandactivecompoundisolated
mitochondria. from Silybum marianum (milk thistle) traditionally used
Allyl alcohol from garlic (Allium sativum), which has to protect from liver injury, could induce apoptosis related
beenusedasatraditionalantimicrobialagentforthousands to mitochondrial Ca2+ influx in C. albicans cells [84, 85].
of years, exerts its antifungal effect through introducing Silibinin could alleviate mitochondrial dysfunction in mice
oxidative stress such as increasing ROS production and modelofcisplatin-inducedacutekidneyinjurythroughSirt3
depletingglutathione.Theknowntargetsofallylalcoholare activation, although in vitro proapoptotic effects through
cytosolic alcohol dehydrogenases Adh1 and Adh2 and the inducingROSproductionhavebeenalsoreported[86,87].
mitochondrial Adh3 [66]. Although allyl alcohol could be Thesafeprofilewithsilibinin,evidencedbymarketedhealth
released after ingestion of garlic, its toxicity, mediated by food and clinical trials, makes silibinin a very promising
acroleintheproductionofwhichiscatalyzedbyalcoholdehy- candidateforantifungaltherapiesagainstCandidainfections
drogenaseinrodents,preventsitsdevelopmentasantifungal althoughthereisstillalongwaytogo[88].
agent[66,67].
Baicalincouldinhibittheactivitiesofenzymesinmito-
5.VirulenceFactors
2+ 2+
chondria (such as Ca -Mg -ATPase, succinate dehydro-
genase, and cytochrome oxidase) and induce cell cycle VirulencefactorscontributingtotheCandidainfectionshold
blockageandapoptosisinC.albicanscells[68].However,in adhesins, virulence enzymes (secreted aspartyl proteinase
mammaliancells(e.g.,CHOcell),baicalincouldreduceROS andphospholipasesfunctioninginhosttissueinvasion)[89],
production[69].Therearealsoreportsshowingthatbaicalin andmorphologicaltransition[90].
inducesapoptosisinhumannon-smalllungcancercellsand
osteosarcomacellsthroughROSproduction[70,71].Baicalin 5.1.Yeast-to-HyphaTransition. Althoughbothbuddingyeast
could protect mitochondria from damage caused by strep- type and hyphal type of C. albicans have been found at
tozotocin and hepatic ischemia/reperfusion and increase the loci of infections, the transition of yeast-to-hypha in
the activity of citrate synthase in rats [72, 73]. Despite the C. albicans is considered to be a major factor involved in
discrepancybetweentherolesofbaicalinindifferentcellsin the colonization, invasion/penetration, virulence, immune
ROS production, the in vivo tests might support the use of evasion,andsurvivalinthehosttissues[91–93].Forinstance,
baicalinasanantifungalcandidate[69,71,73]. most of the hyphal growth of C. albicans could not be
BioMedResearchInternational 5
suppressed by the macrophages after engulfment in vitro surface) [108]. Biofilm, buried in the extracellular matrix
andlysisofmacrophagecausedbypenetrationofhyphawas (ECM),holdsacomplicatedthree-dimensionalarchitecture
also observed [94]. What isworthmentioningisthat,soon consisting mainly of yeast form cells and hyphal cells with
after phagocytosis by macrophages, the hyphal formation broadheterogeneityinspace[15,109].Thespatial,structural,
of C. albicans is required (but not sufficient) for inducing and metabolic heterogeneity of biofilms is considered to
theproinflammatorypyroptosis,akindofprogrammedcell promote influx of nutrients, efflux of waste products, and
death of macrophages mediated by inflammasome, before establishment of microniches, thus facilitating the adaption
othermacrophagesarekilledbytherobusthyphalformation ofbiofilmstothehypoxicenvironment[99,110].Beginning
of C. albicans [95–97]. Although recently identified Candi- withtheadherenceoffungalcellstothesubstratesurface,the
dalysinsecretedbyC.albicanshyphaeplaysavitalroleinthe developmentofbiofilmundergoesproliferation,maturation,
mucosalpathogenesisthroughitscytolyticeffects,noreports and finally dissemination to finish a cycle and the cycle
abouttherelationshipbetweenitandmacrophages’damage could repeat itself to expand the fungal population [15].
havebeenpublished[98].Nonetheless,Candidalysinrenders Cellsinthebiofilmexhibitgreatadvantagesovertheirfree-
a promising antifungal target for C. albicans. Moreover, living parallels in surviving such as increased resistance to
hyphae could also support the complicated characteristic manyantimycoticdrugs(e.g.,C.albicanscellsofbiofilmare
structures of mature biofilms which will be discussed later almost 1000 times resistant to fluconazole than free-living
[99]. Induced by exogenous stressors (such as presence of cells[111])andprotectionofferedbyECM[15].Theelevated
serum and alterations in temperature, pH, levels of oxygen resistancetoantimycoticdrugsandtheabilitytowithstand
and glucose [91], the presence of N-acetyl-D-glucosamine host immune defenses, as well as the role as a reservoir for
(GlcNAc) [100], adherence, and starvation/nutrient limita- continuing infections, of Candida biofilms cause important
tion [92]), filamentation of C. albicans involves underlying clinical consequence and the presence of biofilms increases
alterationsinproteinsynthesisandmetabolicchangeswhich themorbidityandmortalityofC.albicansrelativetostrains
are mainly the RAS1-Cyr1p-cAMP-PKA-EFG1 pathway and that could not form biofilms [99, 112]. Therefore, biofilm
mitogen-activatedproteinkinase(MAPK)signaling[91,92]. formationisconsideredasapotentvirulencefactor[34].Now
Both signaling pathways are governed by the membrane- theCandidabiofilmsattractmoreandmoreattention,which
integratedsmallGTPaseRas1[101]. couldbereflectedbytheincreasingnumberofpublications
Magnololandhonokiol,twokindsofneolignanisolated onCandidabiofilms.
fromtheroot,stem,andbranchbarkofMagnoliaofficinalis, Heatshockproteinsplaykeyrolesinprotectingcellsfrom
could inhibit the yeast-to-hypha transition of C. albicans damage and repairing damage caused by insults, as well as
under many culture conditions. Treatment of magnolol or in the protein synthesis, folding, transport and membrane
honokiol could induce downregulation of components of translocation,andsoon[9].Compromisingthefunctionof
the Ras1-cAMP-Efg1 pathway (such as RAS1, EFG1, TEC1, Hsp90inC.albicansbygeneticmanipulationorpharmaco-
and CDC35 (the orthologue of Cyr1)), as well as reduced logicalmeanscouldreducethedispersalandmaturationof
expression levels of the hypha-specific genes ECE1, HWP1, biofilms as well as increase the sensitivity to drugs used to
and ALS3, while exogenous cAMP could restore the fila- abolishbiofilms[106].SoinhibitorsofHsp90maypresenta
mentousgrowthinthepresenceofthedrugs.Thesesuggest usefulparadigmfortherapyofinfectionscausedbybiofilm.
thatthetransition-inhibitingeffectsofthesetwocompounds In Candida cells of biofilms, increased expression of
may be associated with the suppression of Ras1-cAMP- many genes has been found such as genes involved in
EFG1pathway[102].Curcumincouldalsoinhibittheyeast- protein synthesis, drug transporting, adherence to matrix,
to-hypha transition through targeting the transcriptional and primary metabolism [109]. Genes encoding envelope
suppressorTUP1(thymidineuptake1)[79].Licochalcone-A, proteinssuchasHwp1,Als1,Als3,andSun41playcriticalroles
a bioactive polyphenol from roots of licorice that has been inbiofilmformation[92].
usedasaherbalremedyforhundredsofyears,couldinhibit Although the structures of C. albicans biofilm can be
themorphologicaltransition[103].Thecompoundglabridin disrupted by physical means such as mechanical removal
fromlicoriceandtheanthraquinonepurpurinfrommadder by brushing on the surface of teeth and ultrasound (or
root (Rubia tinctorum L.) could also inhibit the transition sonication) treatment of implants [113], the clearance of C.
[104,105]. albicansisprimarilydependentondrugswhichcouldprevent
Apart from the regulating role in antifungal resistance theformationofbiofilmorabolishthematuredbiofilm.
in planktonic C. albicans, the chaperone Hsp90 can also BiofilmformationofCandidaspp.andotherfungicould
modulate the transition by inhibiting the filamentation via be replicated in 96-well microtiter plates [36] as well as in
cAMP-PKA signaling [106]. Hsp90 deletion in C. albicans animalparadigms[15],whichprovideuswithusefultoolsto
leadstovirulentattenuationinasystemiccandidiasismodel screenpotentialantifungalhits.DerivedfromCinnamomum
[107].SocomesthehypothesisthatinhibitorsofHsp90may zeylanicum,cinnamonoilexhibitsantifungalactivityagainst
exhibitanti-Candidaeffects. C. orthopsilosis and C. parapsilosis through inhibiting the
formationofbiofilmaswellasthegrowthofplanktoniccoun-
5.2. Biofilm Formation. Most infections caused by Candida terparts [114], although the exact mechanism is unknown.
spp. involve biofilms formed on the surfaces of biomate- One of the major components cinnamaldehyde (of the oil)
rials (such as intravascular catheters and prosthetic heart could also inhibit the biofilm formation of clinical isolates
valves) and biotic mucosa (such as oral cavity and wound of C. albicans [115], and moreover it could suppress the
6 BioMedResearchInternational
growth of Aspergillus flavus and Aspergillus oryzae which as Cladonia and Usnea [131], could inhibit the formation
are culprits of food spoilage [116]. Berberine, an alkaloid of Candida biofilms and other virulent traits [132, 133].
from the medicinal plants such as Coptis chinensis and Berberine, from Berberis aquifolium, Hydrastis canadensis,
Hydrastiscanadensis,alsohasantifungalactivitiesagainstC. Phellodendronamurense,hastheantifungalactivitiesagainst
albicansbiofilms,bothaloneandinsynergywithmiconazole fluconazole-resistantCandidaspp.inplanktonicandbiofilm
[117].Licochalcone-Aalsodemonstratedinvitroandinvivo form [134]. Emodin from rhizomes of Rheum palmatum
antifungalactivityagainstC.albicansbiofilms[103].Purpurin couldinhibittheformationofbiofilmsandhyphaldevelop-
also demonstrated antifungal activity against the formation mentofC.albicans[135].
and preformed biofilms of C. albicans, in addition to its
capabilityofinhibitingmorphologicaltransition[104]. 5.3. Other Factors. Virulence in mice caused by C. albi-
Asidefrominhibitingtheyeast-to-hyphatransition,mag- cans mutants deficient in isocitrate lyase 1 (ICL1, a major
nolol and honokiol also inhibit biofilm formation via sup- component of the glyoxylate cycle) is evidently less than
pressingadhesionandgrowthofC.albicansasisevidenced the wide type equivalents, which indicates the involvement
byXTTassayandconfocallaserscanningmicroscopy.These of the glyoxylate cycle in the pathogenesis of candidiasis
twocompoundscouldreducethefungalburdenandprolong [136]. ICL1, as well as malate synthase, is the distinctive
thelifespanofCaenorhabditiselegansinanematodesinfec- enzymethathasnotbeenobservedinmammaliancells;thus
tionmodel[102].Whatismoreimportant,compoundsatthe it may render a unique target for inhibiting the virulence
concentrations used exhibit no adverse effect on the mam- of C. albicans to combat this fungal pathogen. Recently,
malianHSC-T6cellsandnematodes[102].Curcumincould inhibitorsofmalatesynthasedemonstratedantifungaleffect
alsoinhibitthebiofilmformationofC.albicans[118].Thymol against Paracoccidioides species [137], while apigenin, the
(5-methyl-2-(1-methylethyl) phenol), a major essential oil active flavone compound in Chinese herbs such as thyme,
in the herb thyme (Thymus vulgaris L., Lamiaceae) which could inhibit the enzymatic activity of ICL1 in C. albicans
could be applied for treating multiple symptoms including [138, 139]. Rosmarinic acid, the bioactive polyphenol in
bronchitis, whooping cough, and catarrh of the upper res- herbssuchasbasil(Ocimumbasilicum),oregano(Origanum
piratory tract [119, 120], exhibits antifungal activity against vulgare), sage (Salvia officinalis), and Melissa officinalis, has
fluconazole-sensitiveandfluconazole-resistantisolatesofC. also been identified as an inhibitor of ICL1 in C. albicans
albicans [121]. Recent study identified that thymol could [138, 140]. Recent study by Ansari et al. demonstrated that
inhibit the biofilm formation and development, and more- both the enzymatic activity and mRNA expression of ICL1
over this compound could enhance the host antimicrobial andmalatesynthaseofC.albicanscouldbeinhibitedbythe
responsesagainstC.albicansandincreasethelifespanofC. monoterpenoid perillyl alcohol, the active compound from
elegans during the fungal infection [115, 122]. In addition, edibleandmedicinalplantPerillafrutescensL.exB.D.Jacks.
thymolhasshownsynergywithfluconazoleagainstbiofilms (Lamiaceae) which has been used for treating colds, food
[115,123].BaicaleinandaucubinfromPlantagomajor(greater allergy, and depression [141, 142]. Considering the absence
Plantain),aperennialherbusedforwoundhealing,analgesic, of ICL1 in human, the well-tolerated profile in human, and
anti-inflammatory,antioxidant,andinfections,couldinhibit thefactthatPhaseIItrialshavebeenconductedinpatients
thebiofilmformationanddecreasethecellsurfacehydropho- with cancers, perillyl alcohol might serve as an interesting
bicity of C. albicans [124]. Eugenol, the major components candidate for antifungal therapies against C. albicans [143,
ofessentialoilsfromSyzygiumaromaticum(clove),possesses 144].
thecapacitytoinhibitthebiofilmformationandpreformed Similar to Pseudomonas aeruginosa, communication
biofilms, more effective than marketed antifungal drug flu- among fungal cells is often associated with virulence [145].
conazole. This compound could also produce synergistic Quorum sensing means that molecules secreted by the C.
effects with fluconazole [115, 123] and what is more, the albicans cells in response to cell density could affect the
structure-activityrelationshipofthiscompoundisanalyzed behaviors of the cells. The formation of biofilms, hyphal
[125].Anotherphenylpropanoidfromclove,methyleugenol, growth, and virulence factors of C. albicans could also be
also exhibits antifungal effect against fluconazole-resistant regulatedbyquorumsensing[146].Themostfamousquorum
Candidaisolatesandsynergisticeffectwithfluconazole[126]. sensingmoleculeofC.albicansisfarnesol,oneautoregulatory
Antibiofilm activity of menthol from mint, either alone or sesquiterpene alcohol that could prevent the filamentation
in combination with fluconazole, was also identified [123, (throughrepressingtheRas1-cAMP-PKAsignalingpathway
127]. So is the case with geraniol (3,7-dimethylocta-trans- [147]),shrinkthebiofilm(ifaddedbeforeattachmentorafter
2,6-dien-1-ol) [115], an acyclic monoterpene alcohol which formationbutnotduringtheinitialstagesofbiofilmgrowth
could be isolated from many herbs such as Pelargonium [148]),andblockothervirulencefactors[149].Socomesthe
graveolens (Geraniaceae), nutmeg, and ginger [128, 129]. strategythattargetingquorumsensingmoleculesmaycon-
Another compound from Pelargonium graveolens, linalool, tributetotheantifungaltherapies[146].Indeed,thedietary
alsoexhibitsantifungaleffectontheplanktonicandbiofilm flavonoidquercetinisolatedfromedibleandmedicinallichen
cells of C. tropicalis [129]. Carvacrol could also sensitize Usnealongissimicouldsensitizefluconazole-resistantisolate
the Candida biofilms, as well as the planktonic cells, to NBC099tofluconazoleandthiskindofsensitizationcould
fluconazole [130]. Usnic acid (2,6-diacetyl-7,9-dihydroxy- bethequercetin-inducedproductionoffarnesol[146].
8,9b-dimethyl-1,3(2H,9bH)-dibenzo-furandione),themajor AnotherquorumsensingmoleculeproducedbyC.albi-
active component isolated from medicinal lichens such cans, tyrosol, could also affect the development of Candida
BioMedResearchInternational 7
biofilms[150].Thisaromaticalcoholcouldinducethemor- combinations,especiallythesynergisticeffectswithmarketed
phological transition from yeast to hyphae. At high con- drugs [162–164]. An important part of the adjuvants to
centrations (above 200mM), tyrosol could cause reduction antibioticsmightcomefromthepreviouslyundervaluedpart
in biofilms formed by Candida species as well as those by ofchemicalentities,whichhavebeenrecentlytermedasdark
Streptococcusmutans[151]. chemicalmatter(DCM)[165].BecausetheseDCMshowed
ExtracellularhydrolyticenzymesproducedbyC.albicans littleornobioactivityinpreviousresearchestowardshuman
areconsideredasvirulencefactorsliableforthepenetration targets, it may represent a noveland valuable repertoirefor
into and damage to host cells caused by this pathogenic identifying hits and optimizing leads [165]. The machine
fungus [152]. These enzymes include secreted aspartic pro- learning-based synergism prediction may be a promising
teinases, lipases, and hemolysins [34]. Quercetin could methodtoidentifysynergisticeffectsofmarketedantifungal
inhibit the activities of proteinase, esterase, phospholipase, drugsandnaturalproductsisolatedfromtraditionalChinses
and hemolysins of fluconazole-resistant C. albicans strain medicine [162]. Considering new proteins or biological
NBC099[146].Inaddition,thiscompoundcouldalsosyner- processes that might be used as emerging targets such as
gizewithfluconazoleagainstbiofilmbothinvivoandinvitro histone deacetylase and ion homeostasis, compounds from
[153]. TCM might play increasing important and diverse roles in
developingantifungaltherapiesagainstC.albicans.
6.CompoundswithoutIdentifiedMechanism
ConflictsofInterest
Anofinic acid and fomannoxin acid isolated from Gentiana
AlgidashowedweakantifungalactivitiesagainstC.albicans,
The authors declare that there are no conflicts of interest
while the esterification by introducing methyl group into
regardingthepublicationofthisarticle.
thosecompoundscouldenhancetheanti-Candidaactivities
butdecreasetheactivitiesagainsttheCladosporiumcucumer-
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