antifungal compounds against candida infections from traditional chinese...

Review ArticleAntifungal Compounds against Candida Infections fromTraditional Chinese Medicine

Xin Liu1 Zhiming Ma2 Jingxiao Zhang3 and Longfei Yang4

1Eye Center The Second Hospital of Jilin University Changchun 130041 China2Department of Gastrointestinal Nutrition and Hernia Surgery The Second Hospital of Jilin University Changchun 130041 China3Department of Emergency The Second Hospital of Jilin University Changchun 130041 China4Jilin Provincial Key Laboratory on Molecular and Chemical Genetics The Second Hospital of Jilin UniversityChangchun 130041 China

Correspondence should be addressed to Longfei Yang yanglongfeijlueducn

Received 25 August 2017 Revised 25 November 2017 Accepted 6 December 2017 Published 28 December 2017

Academic Editor Nikos Chorianopoulos

Copyright copy 2017 Xin Liu et al This is an open access article distributed under the Creative Commons Attribution License whichpermits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Infections caused by Candida albicans often refractory and with high morbidity and mortality cause a heavy burden on the publichealth while the current antifungal drugs are limited and are associated with toxicity and resistance Many plant-derived moleculesincluding compounds isolated from traditional Chinese medicine (TCM) are reported to have antifungal activity through differenttargets such as cellmembrane cell wallmitochondria and virulence factorsHere we review the recent progress in the anti-Candidacompounds from TCM as well as their antifungal mechanisms Considering the diverse targets and structures compounds fromTCMmight be a potential library for antifungal drug development

1 Introduction

One severe health threat is infections caused by fungalpathogens among which Candida species are the secondmost common fungal pathogen next to Cryptococcus neofor-mans responsible for about 400000 life-threatening infec-tions per annum in the worldwide with a mortality as highas 40 [1 2] Candida spp accounted for 98 of centralvenous catheter-related fungemias in patients with cancer [3]Among the many Candida species Candida albicans is themost common fungal pathogen of human diseases followedbyCandida glabrataCandida parapsilosisCandida tropicalisand Candida krusei [2]

As the major opportunistic fungal pathogen C albicansdwells on the skin in the oral cavity mucosa of gutand urogenital tract as a symbiotic fungus under normalconditions [4] The host could discern the commensal andpathogenic state of C albicans rendering this fungus underthe surveillance of immune system and the bacterial microbeof locales where C albicans colonize also contributes tokeeping this fungus in check [5 6] The host defense againstC albicans relies on a complicated network consisting of

innate and adaptive immune components (eg epithelialcells macrophages neutrophils dendritic cells defensinsand complement)When the hosts encounter lower functionsof immune system (resulting from HIV infection organtransplant and cancer treatment [7]) or disequilibrium ofmicroflora due to the use of antibiotics [8] mucocuta-neous and superficial infections such as oral thrush andvaginitis come up This fungal pathogen could also causelife-threatening systematic infections such as candidemiaOther predisposing factors of Candida infections includediabetes and old age [9] Among the nosocomial bloodstreaminfections infections caused by C albicans are the fourthprevalent [10]

In present the therapeutic drugs for Candida infectionsare limited to five classes of compounds polyenes allylaminesazoles fluoropyrimidines and echinocandins [11] andamphotericin B terbinafine fluconazole 5-fluorocytosineand caspofungin are examples for them [12] Drug resistanceemerges due to pervasive application of antifungal drugssuch as fluconazole and voriconazole for both prophylac-tic and therapeutic purposes [13] Cellular and molecular

HindawiBioMed Research InternationalVolume 2017 Article ID 4614183 12 pageshttpsdoiorg10115520174614183

2 BioMed Research International

mechanisms underlying drug resistancemay include reducedaccumulation of intracellular drugs because of increased drugefflux (such as elevated mRNA levels of members of ABCtransporter superfamily) mutations in genes of target protein(resulting in elevated levels of target protein or reducedaffinity to targets) and modification of metabolism pathways(such as altered synthetic pathway of sterol which plays animportant role in both structure and function of fungalcell wall) [14] Researches indicate extensive regulation ofintracellular processes in response to antifungal drugs Thefungistatic property of some drugs such as azoles and 5-flucytosine also contributes to the emergence of resistance[10] while the formation of biofilm may contribute to andelevate the resistance [15] The paucity of antifungal drugsand the emergence of resistance make it a pressing missionto discover and identify new hits and leads from synthesizedchemicals or natural products Compared to synthesizedchemicals natural products have many advantages such asstructural diversity and relatively low toxicity

Natural products provide a potential source for antifungaldrugs either in their nascent form or as original templates forstructure-optimizing for more effective and safe derivatives[16 17] Among the marketed antibiotics used clinicallyabout 80 are derived fromnatural products [17] TraditionalChinese medicine is composed of mainly herbs that havebeen used for thousands of years Recently single compoundsisolated from many traditional Chinese herbs have beendemonstrated to have various kinds of pharmacological activ-ities such as antibacterial antitumor antiviral and antifungalactivities Considering the present lack of antifungal drugsand the usefulness of traditional Chinese medicine it maybe a promising strategy to develop antifungal agents fromtraditional Chinese medicines Here recent antifungal com-pounds from traditional Chinese medicines will be brieflyreviewed

2 Compounds Targeting Cell Membrane

The plasma membrane keeps the cytoplasm from circum-ambient environment The integrity and fluidity of cellmembranemeans being important to the survival and growthof fungal cells one important reason is that many enzymeschannels and transporters of drugs lie on the cell mem-brane Cell membrane is the location where many metabolicprocesses occur and meanwhile it provides a barrier toenvironmental stresses

Derived from Sambucus williamsii a traditional herbbroadly used for hundreds of years to treat fractures edemaand scratches in East Asian countries (minus)-olivil-91015840-O-120573-D-glucopyranoside exerts its antifungal activity against Calbicans by depolarizing the cell membrane evidenced byinflux of propidium iodide (PI) and elevated fluorescenceof 331015840-dipropylthiacarbocyanine iodide (DiSC

3(5) a cyanine

dye formeasuringmembrane potential) [18]More importantand encouraging is that this compound shows little hemolyticactivity on human erythrocytes [18] Two other components(both are lignans) from the same plant lariciresinol [19]and (+)-pinoresinol show similar anti-Candida effects by

damaging the plasma membrane leading to permeabilization[19 20] The differential effects upon human and fungicells imply that it may act on unique components of fungicells which needs further identification Another compoundisolated from Sambucus williamsii glochidioboside showsantifungal activity similar to that of (minus)-olivil-91015840-O-120573-D-glucopyranoside against C albicans by forming pores oncytoplasmicmembranewith a radius range from 14 to 23 nm[21] One of the products from the secondary metabolismof Trachelospermum asiaticum dihydrodehydrodiconiferylalcohol 91015840-O-120573-D-glucoside could also depolarize the trans-membrane potential via forming pores with radii rangingfrom 074 nm to 14 nm [22] Changes in granularity andsize revealed by the flow cytometry assays also involvesalterations of the membrane properties such as osmolarity[22] However there are no evident causative link betweendisruption of membrane potential and changes of osmolarityand no conclusions about which comes first which remain tobe further investigated

As a component of fungal cell membrane different fromthe mammalian parallel and a critical modulator for differ-entiation and pathogenicity of fungi the glycosphingolipidglycosylceramide in the cell envelopemaybe presents a bettertarget for antifungal therapeutic treatments [23]

Ergosterol plays important roles in regulating the fluidityof the cell membrane and cell division of fungal cells whilethe structural and conformational differences between ergos-terol and sterol (the counterpart of ergosterol in mammaliancells) underlie the antifungalmechanismof the polyenes suchas amphotericin B [12 24] Despite the low bioavailability andhigh toxicity of ergosterol-targeting drugs in humans [25 26]ergosterol still presents a good target for antifungal drugs dueto the importance of cell membrane

Magnolol one of the major pharmacologically activecompounds from Magnolia officinalis which could be usedto ameliorate the symptoms such as anxiety asthma ner-vous disturbance and digestive problems [27] could reducethe content of ergosterol in the widely used C albicansSC5314 [28] Compounds from essential oil of mint suchas menthol menthone and carvone suppress the growthof C albicans through decreasing the contents of ergosterolin cell membrane and the hemolysis caused by them is lessthan that induced by fluconazole [29] The ergosterol levelscould also be decreased by carvacrol (isolated fromOriganumdictamnus L) and thymol which could exert their influenceon the antioxidant defense system increase the membranepermeability block the efflux pumps and thus restore theantifungal susceptibility [30 31] Aside fromCandida speciesantifungal activities of this compound against other fungisuch asMonilinia laxa have been identified [31ndash33]

Transporters such as ABC transporters on cell membranecould induce the efflux of antifungals thus compromising theeffects of drugs Treatment with magnolol could significantlydecrease the efflux of fluconazole thus enhancing the anti-fungal effects of fluconazole [28]

PM-H+ ATPase on cell membrane plays a vital role inkeeping the transmembrane electrochemical proton gradientwhich is important for the obtaining of nutrients Theintercellular pH hemostasis modulated by PM-H+ ATPase is

BioMed Research International 3

of great physiological importance And the enzymatic activityof PM-H+ ATPase is positively correlated with cell viability[29] Carvone menthol and menthone could suppress thePM-H+ ATPase activity presumably the primary cause of theantifungal effects [29]The results also indicated the existenceof targets that could be easily touched by external drugsdespite the fact that more efforts need to be made

3 Compounds Targeting CellWall Components

The structural integrity of cell wall is vital to the survival andgrowth of fungal cells as it provides a shelter from osmoticpressure and other stresses in milieu Recent studies showedthat it likely plays an important role in the colonizationand biofilm formation of C albicans as proteins associatedwith adhesion such as Als1 Als3 and Hwp1 are cell wallproteins [34 35] Damaged cell wall leads to osmotic fragilityof the fungal cell disrupted membrane efflux of cytoplasmiccontents and suppressed growth of fungi [13] Cell wall islacking in mammal cells which makes it a preferential targetfor potential antifungal drugs for safety considerations Thecell wall ofCandida species holds glycoproteins and abundantcarbohydrates among which are largely glucan mannoseand chitin [10] In the following part of this review we willdiscuss the plant-derived antifungal components acting oncell wall elements or on the synthesis of those elements

31 Chitin As one of the major components comprisingfungal cell wall chitin is a long linear homopolymer of 120573-14-linkedN-acetylglucosamine (GlcNAc) and is synthesizedby the incorporation of GlcNAc units from the precursoruridine 51015840-diphospho-N-acetylglucosamine (UDP-GlcNAc)in a reaction catalyzed by chitin synthetase (CHS) [36 37]

Despite the small percentage in the cell wall chitin playsimportant roles in maintaining the mechanical strength ofthe fungal cell wall thus keeping the integrity of the fungalcell wall [38] Damage to the cell wall may be ameliorated bythe elevated quantity of chitin in cell wall due to increasedsynthesis andor decreased degradation of chitin which mayincrease the tolerance to antifungal drugs [38] Since thismaterial does not exist in human cells this presents anattractive target for antifungal therapies [36] The chemicalstructures of the classic inhibitors of CHS namely polyoxinsand nikkomycinsmake themselves be degraded easily in vivoanddifficult to go through the cellmembrane leading to a lowantifungal activity [36 39] This prompts us to find new CHSinhibitors

Plagiochin E derived from liverwort Marchantia poly-morpha L exerts its antifungal effect through inhibiting theexpression of chitin synthetase gene 1 (CHS1) and thereforesuppressing the activity of CHS and subsequent synthesisof chitin both in vivo and in situ [13] Interestingly theexpression of CHS2 and CHS3 gene was upregulated bythis macrocyclic compound [13] However the same groupfound that plagiochin E exposure of C albicans could induceaccumulation of reactive oxygen species (ROS) throughmalfunction of mitochondria while pretreatment with L-cysteine could contribute to the survival of C albicans [40]

These studies indicate that plagiochin Emay exert its antifun-gal activity through diverse currently unknownmechanisms

32 Glucan This carbohydrate polymer together with chitinis the structural component which holds the integrity andphysical strength of the cell wall The production andassembly of glucan in C albicans need a series of enzymesand regulatory networks which are fungal-specific and thusrender some fascinating targets for antifungal therapies [41]The most famous drugs of this kind are echinocandins suchas caspofungin and micafungin which inhibit the synthesisof 120573-13-glucan [10] Although they are fast-acting lesstoxic and fungicidal [10] mutations in 120573-13-glucan synthasethat confer resistance to caspofungin have already emergedRecently a novel terpene antifungal SCY-078 demonstratedfungicidal activity against C albicans through inhibitingglucan synthase [42] Sodium houttuyfonate a derivativefrom Houttuynia cordata Thunb might exert its synergisticeffect with fluconazole through interfering with 120573-13-glucansynthesis and transportation [43]

4 Compounds Targeting Mitochondria

The classical respiratory chains of mitochondria are cen-ters of energy production through oxidative phosphoryla-tion and meanwhile mitochondria are the organelles thatproduce metabolic intermediates used for amino acid andlipid biosynthesis Both energy supply and metabolites areindispensable for the survival and growth of C albicans aswell asmajor cellular event such as yeast-to-hyphal transitionMitochondria are also involved in efflux-mediated resistanceof C albicans to fluconazole [44] while in vitro resistanceof C glabrata to azoles is associated with mitochondrialDNA deficiency [45] Resistance to azole is also likely tobe related with decreased generation of endogenous ROSthat are harmful to DNA proteins and lipids while ROSare mainly generated by enzyme complexes (Complex I andComplex III) in classical respiratory chain as by-products ofselective degradation of mitochondria [44] Elevated levelsof intracellular ROS are involved in the antifungal effects offluconazole and miconazole and ROS also play an importantrole in intrinsic mitochondrial pathway of apoptosis in Calbicans [46 47] Besides the common enzymes in classi-cal respiratory chain in C albicans cells there also existrotenone-insensitive NAD(P)H dehydrogenase and alterna-tive terminal oxidases constituting the cyanide-insensitiverespiratory chain [48ndash50] In addition C albicans and Cparapsilosis have additional respiratory pathway called par-allel respiratory chain [51] The differences between fungaland mammal mitochondrial enzymes also make developingdrugs targeting these enzymes possible [52]This is the case ofsome agrichemicals such as boscalid and carboxin that inhibitthe succinate dehydrogenase in fungal cells [53] Althoughthere are only few studies on drugs targeting specificallymitochondria of Candida spp ME1111 [2-(35-dimethyl-1H-pyrazol-1-yl)-5-methylphenol] did exert its antifungal effectsupon human pathogens Trichophyton mentagrophytes andTrichophyton rubrum through inhibiting succinate dehydro-genase in mitochondria with high selectivity (the IC

50values


for human cells are more than thirty times higher than thatfor fungal cells) [53] In a word mitochondria might be apromising target for antifungal therapies

As an important constituent of many herbs of Berberi-daceae family such as Berberis vulgaris berberine exerts itsantifungal action by induction of mitochondrial dysfunctionand increased ROS generation and its effects are in syn-ergy with fluconazole even in fluconazole-resistant clinicalisolates [54ndash56] Moreover berberine treatment could alsoculminate in disruption of cell wall integrity in C albicans[57] and inhibit the overexpression of drug resistance geneCDR1 induced by fluphenazine [58] Although berberinecould induce apoptosis in many human cells such as HL-60 leukemia cells and thyroid carcinoma cells [59 60]berberine could recover the mitochondrial function inducedby high-fat feeding in a rat model and could decrease thetriglyceride accumulation in the liver in mice [61 62] Italsomarkedly decreased the ROS generation inmitochondria[62] This makes berberine a good candidate for antifungaldevelopment although there are much more to be done

(+)-Medioresinol from the anti-inflammatory analgesicand diuretic herbal plant Sambucus williamsii imposed onC albicans could induce generation of ROS and cell cyclearrest and finally apoptosis [47] Although (+)-medioresinolcould inhibit in vitro the proliferation of mammalian cellssuch as A549 SK-MEL-2 SK-OV-3 and HCT-15 cells at highconcentrations the IC

50values for these cell lines were much

higher than the MIC value against C albicans cells [47 63]In a cohort study in Sweden (+)-medioresinol in food didnot clearly reduce the risk of esophageal and gastric cancersbut at least this compound in diet did not show bad effects[64 65]The safe profile of this ligninmakes it more inspiringalthough there is no report on its effects on mammalianmitochondria

Allyl alcohol from garlic (Allium sativum) which hasbeen used as a traditional antimicrobial agent for thousandsof years exerts its antifungal effect through introducingoxidative stress such as increasing ROS production anddepleting glutathione The known targets of allyl alcohol arecytosolic alcohol dehydrogenases Adh1 and Adh2 and themitochondrial Adh3 [66] Although allyl alcohol could bereleased after ingestion of garlic its toxicity mediated byacrolein the production ofwhich is catalyzed by alcohol dehy-drogenase in rodents prevents its development as antifungalagent [66 67]

Baicalin could inhibit the activities of enzymes in mito-chondria (such as Ca2+-Mg2+-ATPase succinate dehydro-genase and cytochrome oxidase) and induce cell cycleblockage and apoptosis in C albicans cells [68] However inmammalian cells (eg CHO cell) baicalin could reduce ROSproduction [69] There are also reports showing that baicalininduces apoptosis in human non-small lung cancer cells andosteosarcoma cells through ROS production [70 71] Baicalincould protect mitochondria from damage caused by strep-tozotocin and hepatic ischemiareperfusion and increasethe activity of citrate synthase in rats [72 73] Despite thediscrepancy between the roles of baicalin in different cells inROS production the in vivo tests might support the use ofbaicalin as an antifungal candidate [69 71 73]

Shikonin the major active compound isolated fromLithospermum erythrorhizon could induce the endoge-nous ROS production reduce the mitochondrial membranepotential and alter mitochondrial aerobic aspiration [74]In human gastric cancer cells and TT medullary thyroidcarcinoma cells shikonin could also induce ROS productionand mitochondria-mediated apoptosis [75 76] The almostsame cytotoxicity for fungal cells and mammalian cellsmakes shikonin a less attractive candidate for antifungaldevelopment

Curcumin the yellow pigment isolated from the turmeric(the rhizome of the plant Curcuma longa Linn) could alsobe used as an adjunct drug to treat pathogenic microor-ganisms such as Helicobacter pylori methicillin-resistantStaphylococcus aureus (MRSA) and Trypanosoma cruziAntifungal activities against various kinds of fungi such asCandida species Cryptococcus neoformans Aspergillus sppand Sporothrix schenckii have also been demonstrated bythis compound [77 78] Curcumin could increase ROSproduction and apoptosis in C albicans cells either aloneor in synergy with antifungal drugs such as azoles andpolyenes [78 79] In mammalian cells curcumin couldprotect mitochondria from damage and increase the bio-genesis of mitochondria although apoptosis-inducing effectsof curcumin have also been reported in cancer cells [8081] Most importantly this compound could be safe with amaximum tolerance dose of 12000mgday in Phase I clinicaltrials [82] which present an advantage over other antifungalcompounds However the poor oral bioavailability and poorsolubility in aqueous solutions impede its use and promotethe development of methods for delivering curcumin to fightCandida infections [83]

Silibinin the most famous and active compound isolatedfrom Silybum marianum (milk thistle) traditionally usedto protect from liver injury could induce apoptosis relatedto mitochondrial Ca2+ influx in C albicans cells [84 85]Silibinin could alleviate mitochondrial dysfunction in micemodel of cisplatin-induced acute kidney injury through Sirt3activation although in vitro proapoptotic effects throughinducing ROS production have been also reported [86 87]The safe profile with silibinin evidenced by marketed healthfood and clinical trials makes silibinin a very promisingcandidate for antifungal therapies against Candida infectionsalthough there is still a long way to go [88]

5 Virulence FactorsVirulence factors contributing to theCandida infections holdadhesins virulence enzymes (secreted aspartyl proteinaseand phospholipases functioning in host tissue invasion) [89]and morphological transition [90]

51 Yeast-to-Hypha Transition Although both budding yeasttype and hyphal type of C albicans have been found atthe loci of infections the transition of yeast-to-hypha inC albicans is considered to be a major factor involved inthe colonization invasionpenetration virulence immuneevasion and survival in the host tissues [91ndash93] For instancemost of the hyphal growth of C albicans could not be


suppressed by the macrophages after engulfment in vitroand lysis of macrophage caused by penetration of hypha wasalso observed [94] What is worth mentioning is that soonafter phagocytosis by macrophages the hyphal formationof C albicans is required (but not sufficient) for inducingthe proinflammatory pyroptosis a kind of programmed celldeath of macrophages mediated by inflammasome beforeother macrophages are killed by the robust hyphal formationof C albicans [95ndash97] Although recently identified Candi-dalysin secreted by C albicans hyphae plays a vital role in themucosal pathogenesis through its cytolytic effects no reportsabout the relationship between it and macrophagesrsquo damagehave been published [98] Nonetheless Candidalysin rendersa promising antifungal target for C albicans Moreoverhyphae could also support the complicated characteristicstructures of mature biofilms which will be discussed later[99] Induced by exogenous stressors (such as presence ofserum and alterations in temperature pH levels of oxygenand glucose [91] the presence of N-acetyl-D-glucosamine(GlcNAc) [100] adherence and starvationnutrient limita-tion [92]) filamentation of C albicans involves underlyingalterations in protein synthesis and metabolic changes whichare mainly the RAS1-Cyr1p-cAMP-PKA-EFG1 pathway andmitogen-activated protein kinase (MAPK) signaling [91 92]Both signaling pathways are governed by the membrane-integrated small GTPase Ras1 [101]

Magnolol and honokiol two kinds of neolignan isolatedfrom the root stem and branch bark ofMagnolia officinaliscould inhibit the yeast-to-hypha transition of C albicansunder many culture conditions Treatment of magnolol orhonokiol could induce downregulation of components ofthe Ras1-cAMP-Efg1 pathway (such as RAS1 EFG1 TEC1and CDC35 (the orthologue of Cyr1)) as well as reducedexpression levels of the hypha-specific genes ECE1 HWP1and ALS3 while exogenous cAMP could restore the fila-mentous growth in the presence of the drugs These suggestthat the transition-inhibiting effects of these two compoundsmay be associated with the suppression of Ras1-cAMP-EFG1 pathway [102] Curcumin could also inhibit the yeast-to-hypha transition through targeting the transcriptionalsuppressor TUP1 (thymidine uptake 1) [79] Licochalcone-Aa bioactive polyphenol from roots of licorice that has beenused as a herbal remedy for hundreds of years could inhibitthe morphological transition [103] The compound glabridinfrom licorice and the anthraquinone purpurin from madderroot (Rubia tinctorum L) could also inhibit the transition[104 105]

Apart from the regulating role in antifungal resistancein planktonic C albicans the chaperone Hsp90 can alsomodulate the transition by inhibiting the filamentation viacAMP-PKA signaling [106] Hsp90 deletion in C albicansleads to virulent attenuation in a systemic candidiasis model[107] So comes the hypothesis that inhibitors of Hsp90 mayexhibit anti-Candida effects

52 Biofilm Formation Most infections caused by Candidaspp involve biofilms formed on the surfaces of biomate-rials (such as intravascular catheters and prosthetic heartvalves) and biotic mucosa (such as oral cavity and wound

surface) [108] Biofilm buried in the extracellular matrix(ECM) holds a complicated three-dimensional architectureconsisting mainly of yeast form cells and hyphal cells withbroad heterogeneity in space [15 109]The spatial structuraland metabolic heterogeneity of biofilms is considered topromote influx of nutrients efflux of waste products andestablishment of microniches thus facilitating the adaptionof biofilms to the hypoxic environment [99 110] Beginningwith the adherence of fungal cells to the substrate surface thedevelopment of biofilm undergoes proliferation maturationand finally dissemination to finish a cycle and the cyclecould repeat itself to expand the fungal population [15]Cells in the biofilm exhibit great advantages over their free-living parallels in surviving such as increased resistance tomany antimycotic drugs (eg C albicans cells of biofilm arealmost 1000 times resistant to fluconazole than free-livingcells [111]) and protection offered by ECM [15] The elevatedresistance to antimycotic drugs and the ability to withstandhost immune defenses as well as the role as a reservoir forcontinuing infections of Candida biofilms cause importantclinical consequence and the presence of biofilms increasesthe morbidity and mortality of C albicans relative to strainsthat could not form biofilms [99 112] Therefore biofilmformation is considered as a potent virulence factor [34]Nowthe Candida biofilms attract more and more attention whichcould be reflected by the increasing number of publicationson Candida biofilms

Heat shock proteins play key roles in protecting cells fromdamage and repairing damage caused by insults as well asin the protein synthesis folding transport and membranetranslocation and so on [9] Compromising the function ofHsp90 in C albicans by genetic manipulation or pharmaco-logical means could reduce the dispersal and maturation ofbiofilms as well as increase the sensitivity to drugs used toabolish biofilms [106] So inhibitors of Hsp90 may present auseful paradigm for therapy of infections caused by biofilm

In Candida cells of biofilms increased expression ofmany genes has been found such as genes involved inprotein synthesis drug transporting adherence to matrixand primary metabolism [109] Genes encoding envelopeproteins such asHwp1 Als1 Als3 and Sun41 play critical rolesin biofilm formation [92]

Although the structures of C albicans biofilm can bedisrupted by physical means such as mechanical removalby brushing on the surface of teeth and ultrasound (orsonication) treatment of implants [113] the clearance of Calbicans is primarily dependent on drugswhich could preventthe formation of biofilm or abolish the matured biofilm

Biofilm formation of Candida spp and other fungi couldbe replicated in 96-well microtiter plates [36] as well as inanimal paradigms [15] which provide us with useful tools toscreen potential antifungal hits Derived from Cinnamomumzeylanicum cinnamon oil exhibits antifungal activity againstC orthopsilosis and C parapsilosis through inhibiting theformation of biofilm aswell as the growth of planktonic coun-terparts [114] although the exact mechanism is unknownOne of the major components cinnamaldehyde (of the oil)could also inhibit the biofilm formation of clinical isolatesof C albicans [115] and moreover it could suppress the


growth of Aspergillus flavus and Aspergillus oryzae whichare culprits of food spoilage [116] Berberine an alkaloidfrom the medicinal plants such as Coptis chinensis andHydrastis canadensis also has antifungal activities against Calbicans biofilms both alone and in synergy with miconazole[117] Licochalcone-A also demonstrated in vitro and in vivoantifungal activity againstC albicans biofilms [103] Purpurinalso demonstrated antifungal activity against the formationand preformed biofilms of C albicans in addition to itscapability of inhibiting morphological transition [104]

Aside from inhibiting the yeast-to-hypha transitionmag-nolol and honokiol also inhibit biofilm formation via sup-pressing adhesion and growth of C albicans as is evidencedby XTT assay and confocal laser scanning microscopy Thesetwo compounds could reduce the fungal burden and prolongthe lifespan of Caenorhabditis elegans in a nematodes infec-tion model [102] What is more important compounds at theconcentrations used exhibit no adverse effect on the mam-malian HSC-T6 cells and nematodes [102] Curcumin couldalso inhibit the biofilm formation ofC albicans [118]Thymol(5-methyl-2-(1-methylethyl) phenol) a major essential oilin the herb thyme (Thymus vulgaris L Lamiaceae) whichcould be applied for treating multiple symptoms includingbronchitis whooping cough and catarrh of the upper res-piratory tract [119 120] exhibits antifungal activity againstfluconazole-sensitive and fluconazole-resistant isolates of Calbicans [121] Recent study identified that thymol couldinhibit the biofilm formation and development and more-over this compound could enhance the host antimicrobialresponses against C albicans and increase the lifespan of Celegans during the fungal infection [115 122] In additionthymol has shown synergy with fluconazole against biofilms[115 123] Baicalein and aucubin fromPlantagomajor (greaterPlantain) a perennial herb used forwound healing analgesicanti-inflammatory antioxidant and infections could inhibitthe biofilm formation and decrease the cell surface hydropho-bicity of C albicans [124] Eugenol the major componentsof essential oils from Syzygium aromaticum (clove) possessesthe capacity to inhibit the biofilm formation and preformedbiofilms more effective than marketed antifungal drug flu-conazole This compound could also produce synergisticeffects with fluconazole [115 123] and what is more thestructure-activity relationship of this compound is analyzed[125] Another phenylpropanoid from clove methyleugenolalso exhibits antifungal effect against fluconazole-resistantCandida isolates and synergistic effect with fluconazole [126]Antibiofilm activity of menthol from mint either alone orin combination with fluconazole was also identified [123127] So is the case with geraniol (37-dimethylocta-trans-26-dien-1-ol) [115] an acyclic monoterpene alcohol whichcould be isolated from many herbs such as Pelargoniumgraveolens (Geraniaceae) nutmeg and ginger [128 129]Another compound from Pelargonium graveolens linaloolalso exhibits antifungal effect on the planktonic and biofilmcells of C tropicalis [129] Carvacrol could also sensitizethe Candida biofilms as well as the planktonic cells tofluconazole [130] Usnic acid (26-diacetyl-79-dihydroxy-89b-dimethyl-13(2H 9bH)-dibenzo-furandione) the majoractive component isolated from medicinal lichens such

as Cladonia and Usnea [131] could inhibit the formationof Candida biofilms and other virulent traits [132 133]Berberine from Berberis aquifolium Hydrastis canadensisPhellodendron amurense has the antifungal activities againstfluconazole-resistant Candida spp in planktonic and biofilmform [134] Emodin from rhizomes of Rheum palmatumcould inhibit the formation of biofilms and hyphal develop-ment of C albicans [135]

53 Other Factors Virulence in mice caused by C albi-cans mutants deficient in isocitrate lyase 1 (ICL1 a majorcomponent of the glyoxylate cycle) is evidently less thanthe wide type equivalents which indicates the involvementof the glyoxylate cycle in the pathogenesis of candidiasis[136] ICL1 as well as malate synthase is the distinctiveenzyme that has not been observed in mammalian cells thusit may render a unique target for inhibiting the virulenceof C albicans to combat this fungal pathogen Recentlyinhibitors of malate synthase demonstrated antifungal effectagainst Paracoccidioides species [137] while apigenin theactive flavone compound in Chinese herbs such as thymecould inhibit the enzymatic activity of ICL1 in C albicans[138 139] Rosmarinic acid the bioactive polyphenol inherbs such as basil (Ocimum basilicum) oregano (Origanumvulgare) sage (Salvia officinalis) and Melissa officinalis hasalso been identified as an inhibitor of ICL1 in C albicans[138 140] Recent study by Ansari et al demonstrated thatboth the enzymatic activity and mRNA expression of ICL1and malate synthase of C albicans could be inhibited by themonoterpenoid perillyl alcohol the active compound fromedible and medicinal plant Perilla frutescens L ex B D Jacks(Lamiaceae) which has been used for treating colds foodallergy and depression [141 142] Considering the absenceof ICL1 in human the well-tolerated profile in human andthe fact that Phase II trials have been conducted in patientswith cancers perillyl alcohol might serve as an interestingcandidate for antifungal therapies against C albicans [143144]

Similar to Pseudomonas aeruginosa communicationamong fungal cells is often associated with virulence [145]Quorum sensing means that molecules secreted by the Calbicans cells in response to cell density could affect thebehaviors of the cells The formation of biofilms hyphalgrowth and virulence factors of C albicans could also beregulated by quorum sensing [146]Themost famous quorumsensingmolecule ofC albicans is farnesol one autoregulatorysesquiterpene alcohol that could prevent the filamentation(through repressing the Ras1-cAMP-PKA signaling pathway[147]) shrink the biofilm (if added before attachment or afterformation but not during the initial stages of biofilm growth[148]) and block other virulence factors [149] So comes thestrategy that targeting quorum sensing molecules may con-tribute to the antifungal therapies [146] Indeed the dietaryflavonoid quercetin isolated from edible andmedicinal lichenUsnea longissimi could sensitize fluconazole-resistant isolateNBC099 to fluconazole and this kind of sensitization couldbe the quercetin-induced production of farnesol [146]

Another quorum sensing molecule produced by C albi-cans tyrosol could also affect the development of Candida


biofilms [150] This aromatic alcohol could induce the mor-phological transition from yeast to hyphae At high con-centrations (above 200mM) tyrosol could cause reductionin biofilms formed by Candida species as well as those byStreptococcus mutans [151]

Extracellular hydrolytic enzymes produced by C albicansare considered as virulence factors liable for the penetrationinto and damage to host cells caused by this pathogenicfungus [152] These enzymes include secreted aspartic pro-teinases lipases and hemolysins [34] Quercetin couldinhibit the activities of proteinase esterase phospholipaseand hemolysins of fluconazole-resistant C albicans strainNBC099 [146] In addition this compound could also syner-gize with fluconazole against biofilm both in vivo and in vitro[153]

6 Compounds without Identified Mechanism

Anofinic acid and fomannoxin acid isolated from GentianaAlgida showed weak antifungal activities against C albicanswhile the esterification by introducing methyl group intothose compounds could enhance the anti-Candida activitiesbut decrease the activities against theCladosporium cucumer-inum which is a kind of plant pathogenic fungus [154] How-ever no further research about the antifungal mechanismhas been performed since that finding Anofinic acid couldalso be isolated from another traditional Chinese medicineGentiana macrophylla which has been used for long as ther-apies for constipation pains jaundice and rheumatism [155]Another dihydroflavone isolated fromGentianamacrophyllakurarinone could also inhibit the growth of C albicans[155] Nyasol ((Z)-13-bis(4-hydroxyphenyl)-14-pentadiene)isolated from the herbal plant Anemarrhena asphodeloidesBunge (Liliaceae) which has been used in Chinese traditionalmedicine as antipyretic anti-inflammatory antidiabetic andantidepressant agent [156] exhibits antifungal activity againstC albicans alone or in synergy with azoles [157 158] Thiscompound also has activity against other fungal pathogenssuch as A flavus Fusarium oxysporum Pythium ultimumand Rhizoctonia solani to name a few [158 159] Anothercompound from clove isoeugenol also exhibited antifungalactivities against C albicans as well as Aspergillus niger[125] 120572-Terpineol (2-(4-methyl-1-cyclohex-3-enyl) propan-2-ol) fromArtemisia annua could inhibit a series ofCandidaspecies isolated from denture stomatitis patients [160] Thesesquiterpene lactone isolated from Inula racemosa showedgood antifungal activity against Candida species as wellas other human fungal pathogens such as A flavus andGeotrichum candidum [161]

7 Conclusion

In summary many natural compounds from TCM couldexert their anti-Candida activities through different mech-anism providing a big reservoir for developing antifungaltherapies

Combination therapies are capable of increasing theefficacy and preventing the emergence of drug resistanceand many approaches have been adopted to identify effective

combinations especially the synergistic effects withmarketeddrugs [162ndash164] An important part of the adjuvants toantibiotics might come from the previously undervalued partof chemical entities which have been recently termed as darkchemical matter (DCM) [165] Because these DCM showedlittle or no bioactivity in previous researches towards humantargets it may represent a novel and valuable repertoire foridentifying hits and optimizing leads [165] The machinelearning-based synergism prediction may be a promisingmethod to identify synergistic effects of marketed antifungaldrugs and natural products isolated from traditional Chinsesmedicine [162] Considering new proteins or biologicalprocesses that might be used as emerging targets such ashistone deacetylase and ion homeostasis compounds fromTCM might play increasing important and diverse roles indeveloping antifungal therapies against C albicans

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this article

References

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[2] S Giri and A J Kindo ldquoA review of Candida species causingblood stream infectionrdquo Indian Journal ofMedicalMicrobiologyvol 30 no 3 pp 270ndash278 2012

[3] J A Lecciones JW Lee E E Navarro et al ldquoVascular catheter-associated fungemia in patients with cancer analysis of 155episodesrdquoClinical Infectious Diseases vol 14 no 4 pp 875ndash8831992

[4] J Berman ldquoCandida albicansrdquo Current Biology vol 22 no 16pp R620ndashR622 2012

[5] M G Netea L A B Joosten J W M Van Der Meer B-JKullberg and F L Van De Veerdonk ldquoImmune defence againstCandida fungal infectionsrdquoNature Reviews Immunology vol 15no 10 pp 630ndash642 2015

[6] A da Silva Dantas K K Lee I Raziunaite et al ldquoCell biologyof Candida albicansndashhost interactionsrdquo Current Opinion inMicrobiology vol 34 pp 111ndash118 2016

[7] M Richardson and C Lass-Florl ldquoChanging epidemiology ofsystemic fungal infectionsrdquo Clinical Microbiology and Infectionvol 14 no 4 pp 5ndash24 2008

[8] B J Kullberg and M C Arendrup ldquoInvasive candidiasisrdquo TheNew England Journal ofMedicine vol 373 no 15 pp 1445ndash14562015

[9] Y-Y Cao Y-B Cao Z Xu et al ldquocDNA microarray analysisof differential gene expression in Candida albicans biofilmexposed to farnesolrdquo Antimicrobial Agents and Chemotherapyvol 49 no 2 pp 584ndash589 2005

[10] S S W Wong L P Samaranayake and C J Seneviratne ldquoInpursuit of the ideal antifungal agent for Candida infectionshigh-throughput screening of small moleculesrdquoDrug DiscoveryTherapy vol 19 no 11 pp 1721ndash1730 2014

[11] A Rabes S Zimmermann K Reppe et al ldquoThe C-typelectin receptor mincle binds to streptococcus pneumoniae but


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[81] S Mou Z Zhou Y He F Liu and L Gong ldquoCurcumin inhibitscell proliferation and promotes apoptosis of laryngeal cancercells through Bcl-2 and PI3KAkt and by upregulating miR-15ardquo Oncology Letters vol 14 pp 4937ndash4942 2017

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[98] D LMoyes DWilson J P Richardson et al ldquoCandidalysin is afungal peptide toxin critical for mucosal infectionrdquoNature vol532 no 7597 pp 64ndash68 2016

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[100] P A de Castro V L P Bom N A Brown et al ldquoIdentificationof the cell targets important for propolis-induced cell death inCandida albicansrdquo Fungal Genetics and Biology vol 60 pp 74ndash86 2013

[101] J Shareck A Nantel and P Belhumeur ldquoConjugated linoleicacid inhibits hyphal growth in Candida albicans by modulatingRas1p cellular levels and downregulating TEC1 expressionrdquoEukaryotic Cell vol 10 no 4 pp 565ndash577 2011

[102] L Sun K Liao andDWang ldquoEffects ofmagnolol and honokiolon adhesion yeast-hyphal transition and formation of biofilmby candida albicansrdquo PLoS ONE vol 10 no 2 Article IDe0117695 2015

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[104] PW-K Tsang HMHN Bandara andW-P Fong ldquoPurpurinsuppresses Candida albicans Biofilm formation and hyphaldevelopmentrdquo PLoS ONE vol 7 no 11 Article ID e50866 2012

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by hypoxia-inducible factor 1rdquo Annual Review of Cell andDevelopmental Biology vol 15 pp 551ndash578 1999

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[113] T Bjarnsholt O Ciofu S Molin M Givskov and NHoslashiby ldquoApplying insights from biofilm biology to drugdevelopmentmdashcan a new approach be developedrdquo NatureReviews Drug Discovery vol 12 no 10 pp 791ndash808 2013

[114] R H Pires L B Montanari C H G Martins et al ldquoAntican-didal efficacy of cinnamon oil against planktonic and biofilmcultures of Candida parapsilosis and Candida orthopsilosisrdquoMycopathologia vol 172 no 6 pp 453ndash464 2011

[115] M S A Khan and I Ahmad ldquoAntibiofilm activity of certainphytocompounds and their synergy with fluconazole againstCandida albicans biofilmsrdquo Journal of Antimicrobial Chemother-apy vol 67 no 3 pp 618ndash621 2012

[116] D Kocevski M Du J Kan C Jing I Lacanin and H PavlovicldquoAntifungal effect of Allium tuberosum Cinnamomum cassiaand Pogostemon cablin essential oils and their componentsagainst population of Aspergillus speciesrdquo Journal of FoodScience vol 78 no 5 pp M731ndashM737 2013

[117] G-X Wei X Xu and C D Wu ldquoIn vitro synergism betweenberberine and miconazole against planktonic and biofilm Can-dida culturesrdquoArchives of Oral Biolog vol 56 no 6 pp 565ndash5722011

[118] M Shahzad L Sherry R Rajendran C A Edwards E Combetand G Ramage ldquoUtilising polyphenols for the clinical man-agement of Candida albicans biofilmsrdquo International Journal ofAntimicrobial Agents vol 44 no 3 pp 269ndash273 2014

[119] A Raskovic N Pavlovic M Kvrgic et al ldquoEffects ofpharmaceutical formulations containing thyme on carbontetrachloride-induced liver injury in ratsrdquoBMCComplementaryand Alternative Medicine vol 15 no 1 article no 442 2015

[120] L He H Mo S Hadisusilo A A Qureshi and C E ElsonldquoIsoprenoids suppress the growth of murine B16 melanomas invitro and in vivordquo Journal of Nutrition vol 127 no 5 pp 668ndash674 1997

[121] NGuo J Liu XWu et al ldquoAntifungal activity of thymol againstclinical isolates of fluconazole-sensitive and -resistant Candidaalbicansrdquo Journal of Medical Microbiology vol 58 no 8 pp1074ndash1079 2009

[122] C Shu L Sun and W Zhang ldquoThymol has antifungal activityagainst Candida albicans during infection and maintains the

innate immune response required for function of the p38MAPK signaling pathway in Caenorhabditis elegansrdquo Immuno-logic Research vol 64 no 4 pp 1013ndash1024 2016

[123] S C Pemmaraju P A Pruthi R Prasad and V Pruthi ldquoCan-dida albicans biofilm inhibition by synergistic action of terpenesand fluconazolerdquo Indian Journal of Experimental Biology (IJEB)vol 51 no 11 pp 1032ndash1037 2013

[124] K P Shirley L J Windsor G J Eckert and R L Gregory ldquoInvitro effects of Plantago major extract aucubin and baicaleinon Candida albicans biofilm formation metabolic activity andcell surface hydrophobicityrdquo Journal of Prosthodontics vol 26no 6 pp 508ndash515 2017

[125] H Carrasco M Raimondi L Svetaz et al ldquoAntifungal activityof eugenol analogues Influence of different substituents andstudies on mechanism of actionrdquo Molecules vol 17 no 1 pp1002ndash1024 2012

[126] A Ahmad A Khan L A Khan and N Manzoor ldquoIn vitrosynergy of eugenol andmethyleugenol with fluconazole againstclinical Candida isolatesrdquo Journal of Medical Microbiology vol59 no 10 pp 1178ndash1184 2010

[127] M J Saharkhiz M Motamedi K Zomorodian K Pakshir RMiri and K Hemyari ldquoChemical composition antifungal andantibiofilm activities of the essential oil of Mentha piperita LrdquoISRN Pharmaceutics vol 2012 Article ID 718645 6 pages 2012

[128] F Solorzano-Santos andM GMiranda-Novales ldquoEssential oilsfrom aromatic herbs as antimicrobial agentsrdquo Current Opinionin Biotechnology vol 23 no 2 pp 136ndash141 2012

[129] C M C Souza S A Pereira Junior T da Silva Moraes JLDamasceno S Amorim Mendes HJ Dias et al ldquoAntifungalactivity of plant-derived essential oils on Candida tropicalisplanktonic and biofilms cellsrdquoMedical Mycology vol 54 no 5pp 515ndash523 2016

[130] S K Doke J S Raut S Dhawale and S M KaruppayilldquoSensitization of candida albicans biofilms to fluconazole byterpenoids of plant originrdquo The Journal of General and AppliedMicrobiology vol 60 no 5 pp 163ndash168 2014

[131] K Ingolfsdottr ldquoUsnic acidrdquo Phytochemistry vol 61 no 7 pp729ndash736 2002

[132] P Nithyanand R M Beema Shafreen S Muthamil and SKarutha Pandian ldquoUsnic acid inhibits biofilm formation andvirulentmorphological traits of Candida albicansrdquoMicrobiolog-ical Research vol 179 pp 20ndash28 2015

[133] R H Pires R Lucarini and M J S Mendes-Giannini ldquoEffectof usnic acid on Candida orthopsilosis and C parapsilosisrdquoAntimicrobial Agents and Chemotherapy vol 56 no 1 pp 595ndash597 2012

[134] A R Da Silva J B De Andrade Neto C R Da Silvaet al ldquoBerberine antifungal activity in fluconazole-resistantpathogenic yeasts action mechanism evaluated by flow cytom-etry and biofilm growth inhibition in Candida spprdquo Antimi-crobial Agents and Chemotherapy vol 60 no 6 pp 3551ndash35572016

[135] M Janeczko M Masłyk K Kubinski and H GolczykldquoEmodin a natural inhibitor of protein kinase CK2 suppressesgrowth hyphal development and biofilm formation of Candidaalbicansrdquo Yeast vol 34 no 6 pp 253ndash265 2017

[136] M C Lorenz and G R Fink ldquoThe glyoxylate cycle is requiredfor fungal virulencerdquoNature vol 412 no 6842 pp 83ndash86 2001

[137] F G Costa B R Da Silva Neto R L Goncalves et al ldquoAlka-loids as inhibitors of malate synthase from paracoccidioidesspp Receptor-ligand interaction-based virtual screening and


molecular docking studies antifungal activity and the adhesionprocessrdquoAntimicrobial Agents and Chemotherapy vol 59 no 9pp 5581ndash5594 2015

[138] H-L Cheah V Lim andD Sandai ldquoInhibitors of the glyoxylatecycle enzyme ICL1 in Candida albicans for potential use asantifungal agentsrdquo PLoS ONE vol 9 no 4 Article ID e959512014

[139] J Madunic I V Madunic G Gajski J Popic and V Garaj-Vrhovac ldquoApigenin a dietary flavonoid with diverse anticancerpropertiesrdquo Cancer Letters vol 413 pp 11ndash22 2018

[140] A Corral-Lugo A Daddaoua A Ortega M Espinosa-Urgeland T Krell ldquoRosmarinic acid is a homoserine lactone mimicproduced by plants that activates a bacterial quorum-sensingregulatorrdquo Science Signaling vol 9 no 409 article no ra1 2016

[141] M A Ansari Z Fatima K Ahmad and S Hameed ldquoMonoter-penoid perillyl alcohol impairs metabolic flexibility of Candidaalbicans by inhibiting glyoxylate cyclerdquo Biochemical and Bio-physical Research Communications 2017

[142] L Duelund A Amiot A Fillon and O G Mouritsen ldquoInflu-ence of the active compounds of Perilla frutescens leaves onlipid membranesrdquo Journal of Natural Products vol 75 no 2 pp160ndash166 2012

[143] J Ma J Li K S Wang et al ldquoPerillyl alcohol efficientlyscavenges activity of cellular ROS and inhibits the translationalexpression of hypoxia-inducible factor-1120572 via mTOR4E-BP1signaling pathwaysrdquo International Immunopharmacology vol39 pp 1ndash9 2016

[144] G Liu KOettel H Bailey et al ldquoPhase II trial of perillyl alcohol(NSC 641066) administered daily in patients with metastaticandrogen independent prostate cancerrdquo Investigational NewDrugs vol 21 no 3 pp 367ndash372 2003

[145] J E Nett R Zarnowski J Cabezas-Olcoz et al ldquoHost con-tributions to construction of three device-associated Candidaalbicans biofilmsrdquo Infection and Immunity vol 83 no 12 pp4630ndash4638 2015

[146] B N Singh D K Upreti B R Singh et al ldquoQuercetin sensitizesfluconazole-resistant Candida albicans to induce apoptotic celldeath by modulating quorum sensingrdquo Antimicrobial Agentsand Chemotherapy vol 59 no 4 pp 2153ndash2168 2015

[147] A Davis-Hanna A E Piispanen L I Stateva andD A HoganldquoFarnesol and dodecanol effects on the Candida albicans Ras1-cAMP signalling pathway and the regulation of morphogene-sisrdquoMolecular Microbiology vol 67 no 1 pp 47ndash62 2008

[148] C J Nobile J E Nett A D Hernday et al ldquoBiofilm matrixregulation by Candida albicans Zap1rdquo PLoS Biology vol 7 no6 Article ID e1000133 2009

[149] A Deveau and D A Hogan ldquoLinking quorum sensing regu-lation and biofilm formation by Candida albicansrdquo Methods inMolecular Biology vol 692 pp 219ndash233 2011

[150] M A S Alem M D Y Oteef T H Flowers and L J DouglasldquoProduction of tyrosol by Candida albicans biofilms and its rolein quorum sensing and biofilm developmentrdquo Eukaryotic Cellvol 5 no 10 pp 1770ndash1779 2006

[151] L S Arias A C B Delbem R A Fernandes D B Barbosa andD R Monteiro ldquoActivity of tyrosol against single and mixed-species oral biofilmsrdquo Journal of Applied Microbiology vol 120no 5 pp 1240ndash1249 2016

[152] M Yordanov P Dimitrova S Patkar L Saso and N IvanovskaldquoInhibition of Candida albicans extracellular enzyme activityby selected natural substances and their application in Candidainfectionrdquo Canadian Journal of Microbiology vol 54 no 6 pp435ndash440 2008

[153] M Gao H Wang and L Zhu ldquoQuercetin assists fluconazoleto inhibit biofilm formations of fluconazole-resistant candidaalbicans in in vitro and in vivo antifungal managements ofvulvovaginal candidiasisrdquoCellular Physiology and Biochemistryvol 40 no 3-4 pp 727ndash742 2016

[154] M Girardot and C Imbert ldquoNovel strategies against Candidabiofilms interest of synthetic compoundsrdquo FutureMicrobiologyvol 11 no 1 pp 69ndash79 2016

[155] H H Lara D G Romero-Urbina C Pierce J L Lopez-RibotM J Arellano-Jimenez and M Jose-Yacaman ldquoEffect of silvernanoparticles on Candida albicans biofilms an ultrastructuralstudyrdquo Journal of Nanobiotechnology vol 13 no 1 article no 912015

[156] L-X Ren Y-F Luo X Li D-Y Zuo and Y-L WuldquoAntidepressant-like effects of sarsasapogenin from Anemar-rhena asphodeloides Bunge (Liliaceae)rdquo Biological amp Pharma-ceutical Bulletin vol 29 no 11 pp 2304ndash2306 2006

[157] Y Iida K-BOhM SaitoHMatsuoka andHKurata ldquoIn vitrosynergism between nyasol an active compound isolated fromanemarrhena asphodeloides and azole agents against Candidaalbicansrdquo Planta Medica vol 66 no 5 pp 435ndash438 2000

[158] H J Park J Y Lee S S Moon and B K Hwang ldquoIsolation andanti-oomycete activity of nyasol from Anemarrhena asphode-loides rhizomesrdquo Phytochemistry vol 64 no 5 pp 997ndash10012003

[159] Y Iida K-BOhM Saito et al ldquoDetection of antifungal activityin Anemarrhena asphodeloides by sensitive BCT method andisolation of its active compoundrdquo Journal of Agricultural andFood Chemistry vol 47 no 2 pp 584ndash587 1999

[160] M N Gallucci M E Carezzano M M Oliva et al ldquoIn vitroactivity of natural phenolic compounds against fluconazole-resistant Candida species a quantitative structure-activity rela-tionship analysisrdquo Journal of Applied Microbiology vol 116 no4 pp 795ndash804 2014

[161] R X Tan H Q Tang J Hu and B Shuai ldquoLignans andsesquiterpene lactones from Artemisia sieversiana and Inularacemosardquo Phytochemistry vol 49 no 1 pp 157ndash161 1998

[162] J Wildenhain M Spitzer S Dolma et al ldquoPrediction of syner-gism from chemical-genetic interactions by machine learningrdquoCell Systems vol 1 no 6 pp 383ndash395 2015

[163] M Spitzer N Robbins and G D Wright ldquoCombinatorialstrategies for combating invasive fungal infectionsrdquo Virulencevol 8 no 2 pp 169ndash185 2017

[164] G D Wright ldquoAntibiotic adjuvants rescuing antibiotics fromresistancerdquo Trends in Microbiology vol 24 no 11 pp 862ndash8712016

[165] A M Wassermann E Lounkine D Hoepfner et al ldquoDarkchemical matter as a promising starting point for drug leaddiscoveryrdquoNature Chemical Biology vol 11 no 12 pp 958ndash9662015

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 201


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



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ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

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Hindawi Publishing Corporationhttpwwwhindawicom

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Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


mechanisms underlying drug resistancemay include reducedaccumulation of intracellular drugs because of increased drugefflux (such as elevated mRNA levels of members of ABCtransporter superfamily) mutations in genes of target protein(resulting in elevated levels of target protein or reducedaffinity to targets) and modification of metabolism pathways(such as altered synthetic pathway of sterol which plays animportant role in both structure and function of fungalcell wall) [14] Researches indicate extensive regulation ofintracellular processes in response to antifungal drugs Thefungistatic property of some drugs such as azoles and 5-flucytosine also contributes to the emergence of resistance[10] while the formation of biofilm may contribute to andelevate the resistance [15] The paucity of antifungal drugsand the emergence of resistance make it a pressing missionto discover and identify new hits and leads from synthesizedchemicals or natural products Compared to synthesizedchemicals natural products have many advantages such asstructural diversity and relatively low toxicity

Natural products provide a potential source for antifungaldrugs either in their nascent form or as original templates forstructure-optimizing for more effective and safe derivatives[16 17] Among the marketed antibiotics used clinicallyabout 80 are derived fromnatural products [17] TraditionalChinese medicine is composed of mainly herbs that havebeen used for thousands of years Recently single compoundsisolated from many traditional Chinese herbs have beendemonstrated to have various kinds of pharmacological activ-ities such as antibacterial antitumor antiviral and antifungalactivities Considering the present lack of antifungal drugsand the usefulness of traditional Chinese medicine it maybe a promising strategy to develop antifungal agents fromtraditional Chinese medicines Here recent antifungal com-pounds from traditional Chinese medicines will be brieflyreviewed

2 Compounds Targeting Cell Membrane

The plasma membrane keeps the cytoplasm from circum-ambient environment The integrity and fluidity of cellmembranemeans being important to the survival and growthof fungal cells one important reason is that many enzymeschannels and transporters of drugs lie on the cell mem-brane Cell membrane is the location where many metabolicprocesses occur and meanwhile it provides a barrier toenvironmental stresses

Derived from Sambucus williamsii a traditional herbbroadly used for hundreds of years to treat fractures edemaand scratches in East Asian countries (minus)-olivil-91015840-O-120573-D-glucopyranoside exerts its antifungal activity against Calbicans by depolarizing the cell membrane evidenced byinflux of propidium iodide (PI) and elevated fluorescenceof 331015840-dipropylthiacarbocyanine iodide (DiSC

3(5) a cyanine

dye formeasuringmembrane potential) [18]More importantand encouraging is that this compound shows little hemolyticactivity on human erythrocytes [18] Two other components(both are lignans) from the same plant lariciresinol [19]and (+)-pinoresinol show similar anti-Candida effects by

damaging the plasma membrane leading to permeabilization[19 20] The differential effects upon human and fungicells imply that it may act on unique components of fungicells which needs further identification Another compoundisolated from Sambucus williamsii glochidioboside showsantifungal activity similar to that of (minus)-olivil-91015840-O-120573-D-glucopyranoside against C albicans by forming pores oncytoplasmicmembranewith a radius range from 14 to 23 nm[21] One of the products from the secondary metabolismof Trachelospermum asiaticum dihydrodehydrodiconiferylalcohol 91015840-O-120573-D-glucoside could also depolarize the trans-membrane potential via forming pores with radii rangingfrom 074 nm to 14 nm [22] Changes in granularity andsize revealed by the flow cytometry assays also involvesalterations of the membrane properties such as osmolarity[22] However there are no evident causative link betweendisruption of membrane potential and changes of osmolarityand no conclusions about which comes first which remain tobe further investigated

As a component of fungal cell membrane different fromthe mammalian parallel and a critical modulator for differ-entiation and pathogenicity of fungi the glycosphingolipidglycosylceramide in the cell envelopemaybe presents a bettertarget for antifungal therapeutic treatments [23]

Ergosterol plays important roles in regulating the fluidityof the cell membrane and cell division of fungal cells whilethe structural and conformational differences between ergos-terol and sterol (the counterpart of ergosterol in mammaliancells) underlie the antifungalmechanismof the polyenes suchas amphotericin B [12 24] Despite the low bioavailability andhigh toxicity of ergosterol-targeting drugs in humans [25 26]ergosterol still presents a good target for antifungal drugs dueto the importance of cell membrane

Magnolol one of the major pharmacologically activecompounds from Magnolia officinalis which could be usedto ameliorate the symptoms such as anxiety asthma ner-vous disturbance and digestive problems [27] could reducethe content of ergosterol in the widely used C albicansSC5314 [28] Compounds from essential oil of mint suchas menthol menthone and carvone suppress the growthof C albicans through decreasing the contents of ergosterolin cell membrane and the hemolysis caused by them is lessthan that induced by fluconazole [29] The ergosterol levelscould also be decreased by carvacrol (isolated fromOriganumdictamnus L) and thymol which could exert their influenceon the antioxidant defense system increase the membranepermeability block the efflux pumps and thus restore theantifungal susceptibility [30 31] Aside fromCandida speciesantifungal activities of this compound against other fungisuch asMonilinia laxa have been identified [31ndash33]

Transporters such as ABC transporters on cell membranecould induce the efflux of antifungals thus compromising theeffects of drugs Treatment with magnolol could significantlydecrease the efflux of fluconazole thus enhancing the anti-fungal effects of fluconazole [28]

PM-H+ ATPase on cell membrane plays a vital role inkeeping the transmembrane electrochemical proton gradientwhich is important for the obtaining of nutrients Theintercellular pH hemostasis modulated by PM-H+ ATPase is












50values




































7 Conclusion






References























































































































































































Volume 201






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












50values




































7 Conclusion






References























































































































































































Volume 201






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































7 Conclusion






References























































































































































































Volume 201






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology












































































































































































Volume 201






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

antifungal compounds against candida infections from traditional chinese...

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