Is the emergence of fungal resistance to medical triazoles related to their use in the agroecosystems? A mini review

h tt p : / / w w w . b j m i c r o b i o l . c o m . b r /

Review

Is

the

emergence

of

fungal

resistance

to

medical

triazoles

related

to

their

use

in

the

agroecosystems?

A

mini

review

Aícha

Daniela

Ribas

e

Ribas

_,

_Pierri

_Spolti

_,

_Emerson

_Medeiros

_Del

_Ponte

_,

Katarzyna

Zawada

Donato

_,

_Henri

_Schrekker

_,

_Alexandre

_Meneghello

_Fuentefria

c_{InstitutodeQuímica,UFRGS,PortoAlegre,RS,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received26November2014 Accepted4March2016 Availableonline7July2016 AssociateEditor:CarlosPelleschi Taborda

Keywords:

Cross-resistance

Emergingfungalpathogens Fungicidesensitivity Agriculture

Medicine

a

b

s

t

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t

Triazolefungicidesareusedbroadlyforthecontrolofinfectiousdiseasesofbothhumans andplants.Thesurgeinresistancetotriazolesamongpathogenicpopulationsisan emer-gent issue both in agriculture and medicine. The non-rational use of fungicides with site-specific modesofaction, suchasthetriazoles,mayincreasetheriskofantifungal resistancedevelopment.Inthemedicalfield,thesurgeofresistantfungalisolateshasbeen relatedtotheintensiveandrecurrenttherapeuticuseofalimitednumberoftriazolesfor thetreatmentandprophylaxisofmanymycoses.Similaritiesinthemodeofactionof tri-azolefungicidesusedinthesetwofieldsmayleadtocross-resistance,thusexpandingthe spectrumofresistancetomultiplefungicidesandcontributingtotheperpetuationof resis-tantstrainsintheenvironment.Theemergenceoffungicide-resistantisolatesofhuman pathogenshasbeenrelatedtotheexposuretofungicidesusedinagroecosystems. Exam-plesincludespeciesofcosmopolitanoccurrence,suchasFusariumandAspergillus,which causediseasesinbothplantsandhumans.Thisreviewsummarizestheinformationabout themostimportanttriazolefungicidesthatarelargelyusedinhumanclinicaltherapyand agriculture.Weaimtodiscusstheissuesrelatedtofungicideresistanceandthe recom-mendedstrategiesforpreventingtheemergenceoftriazole-resistantfungalpopulations capableofspreadingacrossenvironments.

©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

∗ _{Correspondingauthorat:ProgramadePósGraduac¸ãoemMicrobiologiaAgrícolaedoAmbienteandProgramadePósGraduac¸ãoem}

CiênciasFarmacêuticas,UniversidadeFederaldoRioGrandedoSul,PortoAlegre,Brazil. E-mail:alexandre.fuentefria@ufrgs.br(A.M.Fuentefria).

http://dx.doi.org/10.1016/j.bjm.2016.06.006

1517-8382/©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Fungicides are a key component in human therapy and thecontrolofplantdiseasescausedbyfungithatthreaten human health and crop production.1–5 _{Among the several}

typesoffungicides,theazolegroup(triazoleand imidazole derivatives)was first introduced inthe 1970s.3 _Sincethen,

azoles, especially the triazoles, have been widely used for thecontroloffungal diseasesofseveralplantsandhuman mycoses.6–8 _{As opposed to other systemic fungicides, the}

specific site of action of triazoles is an inherent advan-tagethathasledtoimprovedcontrolefficacy ofthetarget fungus.9,10 _{However,experiencehasshownthatthese}

com-poundsarepronetoresistanceinthepathogenicpopulation, especiallywithoutthe followingofrecommended practices that are aimed at prolonging the effectiveness of these fungicides.9,11,12

Inthiscontext,theefficacy oftriazolefungicidescanbe affected due to cross-resistance or when an isolate devel-ops resistance to all fungicides in a chemical group.13,14

Someauthorshavealsosuggestedthatcross-and multidrug-resistance may be driving forces in the development of resistanceinfungithatareattheinterfacesof agroecosys-tem,domestic,andhospitalenvironments.15,16 Forinstance, emergingfungiinclinicalenvironmentsincludesaprophytic orplantpathogenicfungithathavepreviouslyexposedto tri-azolefungicidesandendupspreadingintotheenvironment andinfectinghumans.6,17–19

Inthisminireview,wesummarizekeyaspectsofthe triaz-olesfortherapeuticuseanddiscussthepossiblelinkbetween triazole-resistantclinicalisolatesandthewidespreaduseof triazolefungicidesforthecontroloffungaldiseases,which wouldhaveamajorimpactinagriculture.

Basicaspectsandtherapeuticuseoftriazoles

Theazole fungicides are ofsynthetic origin and are char-acterized by the presence of an aromatic five-membered heterocycle.Theseincludetriazoles(twocarbon atomsand threenitrogenatoms),imidazoles(threecarbonatomsand twonitrogenatoms),andthiazoles(threecarbonatoms,one nitrogenatomandonesulfuratom).20_{Thecharacteristicsof}

the azolerings, whichare distinguished bythe number of nitrogenandsulfuratoms, changethe physicaland chem-icalproperties, toxicity, and therapeuticefficacies of these compounds.21_{Therefore,theadditionofdifferentsubstitutes}

tothepristine1,2,4-triazolemoleculeinfluencesitsfungicide orfungistaticeffect.

Triazoles affect the biosynthesis ofergosterol, a funda-mentalcomponent of the fungal cell plasma membrane.22

Themaintarget ofantifungalazole drugsislanosterol 14-␣ demethylase (Erg11 protein),a cytochrome P450 enzyme that is involved in the conversion of lanosterol to 4,4-dimethylcholesta-8(9),14,24-trien-3␤-ol.Theazoleagentslink tothisenzymeusingthearomaticfive-memberedheterocycle andtherebyinhibitthecytochromeP450catalyticactivity.9,23

Theabsence ofergosterol andthe increaseofintermediate compoundsalterfungal membraneintegrityaswellascell morphology,whichinhibitsfungalgrowth.24,25

Triazolesareamongthemostcommonsystemicfungicides usedinthecontrolofplantdiseases.Triazolesareabsorbed and translocated in the plant, wheretheyact preventively (beforeinfection)orcuratively(inthepresenceofsymptoms) byaffectinggermtubeandappressoriaformationor hausto-riadevelopmentand/ormycelialgrowth.26,27_{Bywideningthe}

windowofprotectionbeyondprotectantfungicides,whichact onlypreventativelyandarenottranslocated,theadvantages oftriazolesrepresentabreakthroughinincreasingthe produc-tivityofvariouscropsaffectedbyfungaldiseases.2_Arounda

thirdofallfungicidesusedfortheprotectionofcropyields includetriazoles,amongwhichmorethan99%areinhibitors ofdemethylation(DMI).28_{However,triazolefungicidesarealso}

knowntopresentlong-termstability,allowingthemtoremain activeincertainecologicalniches,suchassoilandwater,for severalmonths.2,29

Thenumberofantifungalsavailableinthemedicalfieldfor thetreatmentofsystemicinfectionsisrelativelylimited com-paredtothoseusedforcontrollingdiseasesinplants,which ismainlyduetoproblemsrelatedtoerraticefficacy,drug tox-icity,andintrinsicresistance.30_{Thesecompoundsareusually}

effectiveinbothtopicalandprophylactictreatmentsof inva-sivefungalinfections.31_{However,newtriazolesthatareless}

toxic tohumans and withmorespecifictargets have been investigated.32–34_{Thefirstgenerationoftriazolesforhuman}

therapy included itraconazoleand fluconazole.The second generationisrepresentedbyvoriconazoleandposaconazole, whichprovedtobelesstoxic,safer,andwithabroader spec-trum ofactivity, including activity against fungi that were resistanttothepreviousgeneration.35,36_Presently,

isavucona-zole,ravuconazole,and albaconazolearebeinginvestigated inphaseIIIclinicaltrialsasextended-spectrumtriazoleswith fungicidalactivityagainstawidenumberofclinically impor-tantfungi.

Developmentandmonitoringoftriazoleresistance

Thedevelopmentofresistancetotriazolesasaresultof selec-tivepressurebythecontinueduseofregularorsub-regular dosagesoffungicideistypicallyquantitativeandexpressedby agradualchangeinthefrequencyofresistantisolates.10_The

mainmechanisms involvedhave been reviewedandrelate to the overexpressionofthe CYP51gene duetomutations (insertions or duplications)in the promoter region and an increaseinmoleculareffluxbyABCtransporterscausedbythe overexpressionofgenescodingformembranetransport.9,37,38

Recently,a study that examinedA. fumigatusisolates from arangeofclinicalenvironmentssuggestedpointmutations ofCYP51andTR34/L98Hgenomicregionsinisolatesobtained

frompatientswithlongtermuseoftriazole-basedtherapyfor thetreatmentofchronicaspergillosis.16

Akey elementinthesustainableuse offungicidesisto monitorthesensitivityofthepathogenpopulationtoa cer-taincompound.39–41_{Thereareanumberofdirectandindirect}

methodsrecommendedforspecificfungithatare aimedat estimatingtheEC50(effectiveconcentrationatwhich50%of

fungalgrowthisinhibited)andMIC(minimuminhibitory con-centration)values.10,42–45

In the medical field,the surveillance and preventionof resistance toantifungalagentshave been subjectto many

Table1–Pathogenicfungiwithintrinsicordevelopedresistancetotriazolesforhumantherapeuticuse.

Triazole Fungi References

Itraconazole Aspergillusfumigatus;Fusariumsolani;F.oxysporum;Zygomycetes;Candidaspp. 83–87,63

Fluconazole Candidaspp.;Saccharomycescerevisiae;Trichosporonspp.;Fusariumsolani;F.oxysporum; Scedosporiumspp.;Penicilliumspp.;Bipolarisaustraliensis;B.hawaiiensis;B.spicifera; Aspergillusspp.;Dermatophytes;Zygomycetes;dimorphicfungi;Cryptococcusneoformans

73,84,85,88–93

Voriconazole Aspergillusfumigatus;ZygomycetesTrichosporonspp.;Penicilliumspp. 86,87,94,95

Posaconazole Aspergillusfumigatus 96

Ravuconazole Fusariumsolani;F.oxysporum;Zygomycetes;Pseudallescheriaspp.;Scedosporiumspp.; Acremoniumspp.;Sporothrixschenckii;Scopulariopsisspp.;Paecilomycesspp.

20,34

Albaconazole Fusariumsolani;Zygomycetes 34

Isavuconazole Aspergillusfumigatus 97

restrictive actions in recent years. More specifically, the FDA (Food and Drug Administration) and the EMA (Euro-pean Medicines Agency) regulate and approve the use of antimicrobialsinNorthAmericaand Europe,respectively.46

Simultaneously,theClinicalandLaboratoryStandards Insti-tute(CLSI),together withthe Subcommittee on Antifungal SusceptibilityTesting(AFST)oftheEuropeanCommitteefor AntimicrobialSusceptibilityTesting(EUCAST),publishinvitro

testprotocolsperiodicallyformonitoringfungisensibilityto antifungalagentsofclinicalandveterinaryuse.Theseactions allowforthestandardizationofparametersfortheevaluation ofinvitroresistanceinthelaboratory.However,theseactions andprotocolsdonotinvolvethemonitoringofresistanceof plantpathogenicfungi,thuschallengingtheuseofantifungal agentsinclinicaltherapy.

Inagriculture,theFungicideResistanceActionCommittee (FRAC),a technicalgroup maintainedby the industry, pro-videsguidelinesforthemanagementoffungicideresistance, suchastheneedtoestimateabaselineresistancelevelin iso-latessampledfromthepopulationpriortothecommercialuse ofafungicide.47 _{During commercialuse, reportsoffailures}

indiseasecontrolanddetectionofresistantisolates(those withsensitivitylevelslowerthanthebaseline)areindicators oftheriskofdevelopingfungicideresistance.47_{Periodically,}

informationisprovidedbytheFRACabouttheriskofplant pathogensthatrangesfromlowtohigh.Currently,many stud-ies are known that reportsteadily increasingresistance to triazolesinplantpathogenicfungi.48

Triazoleresistanceinclinicalisolatesandagriculturaluse

In the medicalfield, the first reportof DMI’sresistance in

A. fumigatus isolates dates back more than three decades ago. However, the resistance to itraconazole by Aspergillus

spp. from the clinical environment was first reported in 1997 for three isolates obtained from California in the late1980s.49 _{Theprescription oftriazoles as a preferential}

choice for the treatment of patients with respiratory dis-easeshasbeenconsideredtocontributetothedevelopment of resistance to this group of fungicides.10,50,51

Multidrug-resistance (MDR)52 _{is considered to be the cause of the}

failure of a wide range of antifungal agents available on the market.53,54 _{As an emergent fungus in clinical}

envi-ronments, A. fumigatus holds a history of cross-resistance andmulti-resistancetoazoles.55_{Itisprobablethatmillions}

of people are not effectively treated due to infections by

fungiexhibitingantifungalresistance,amongwhich4.8 mil-lion cases are related only to the species of Aspergillus.56

The triazole antifungals commonly used in the medical field for the treatment of fungal diseases and pathogens that have exhibited some level of resistance are listed in

Table1.

Ithasbeenshownthatexposureofenvironmentalfungi to triazolefungicides may cause shiftsfrom susceptibleto resistant populations,especiallyintheabsence ofadaptive costs which may facilitatethe spread of resistant popula-tions into diverse environments.57 _{Thesurge of“emerging}

fungi”inthemedicalfieldorfungithatareotherwiseharmless tohumans,suchasthezygomycetesandotherhyaline fila-mentousfungi,2,57_{hasledsomeauthorstohypothesizethat}

othermechanismsmaybeleadingtoresistance,suchasthe largeamountoffungicidesusedinagroecosystems.7,58,59_This

hypothesiswasinitiallysuggestedbystudiesconductedinthe Netherlands13 _{and later corroboratedby studiesconducted}

inSpain,60_Belgium,13_Norway,13_{GreatBritain,}61_Denmark,62

France,63_China,64_Italy,65_Austria,65_andIndia.28

A few studies have jointly examined the sensitivity of isolatesthat cause diseases inbothplantsand humans to triazoles.Thesestudiessuggestedthattheselectionof fungi-cideswithasimilarmodeofactionasthoseusedinhuman drug therapyfortriazole-resistantisolatescould contribute tothe developmentofmulti-resistantpopulations.66,67 _The

developmentofcross-resistancetotriazolesandthelow num-beroftriazolesrecommendedforhumantherapyrelativeto thehighnumber oftriazolesusedinagriculturemayaffect triazoleefficacyforhumantherapy.6,10_{Forinstance,the}

fun-gusColletotrichumgraminicolathatcausesanthracnoseofcorn plants is an emerging pathogen in humans. Resistance to tebuconazoleaswellastomultipleotherazoleantifungalshas beenreportedinplantpathogenicpopulationsusedin clini-calmedicine.68,69 _{Similarly,cross-resistancetotriazoleswas}

observedinclinicalisolatesofCandidaalbicansandagricultural environmentalyeasts.70

Several otherfungihavebeenfoundinassociationwith human and animal diseases, including species of several genera such as Bipolaris, Macrophomina, Aspergillus, Fusa-rium,AlternariaandMucor18,71–73_{(Table2).Thepathogenicity}

of clinical isolates of the Fusarium solani species complex was confirmed in plants of the Cucurbitacea family, which exhibitedsimilaraggressivenesstoisolatesoriginatingfrom diseasedplants.17_{Criptococcusneoformansisalsofoundin}

Table2–Maingeneraoffungireportedasthecausativeagentsofdiseasesinplantsandinhumans.

Genus Species References

Fusarium F.dimerum;F.verticilliodies;F.solani;F.oxysporium;F.gramminearum;F.poae;F. sporotrichoides;F.culmorum

18,98,99

Alternaria A.alternate 100,101

Aspergillus A.flavus;A.par B.asiticus;A.terreus

18,98,102–104

Curvularia C.lunata 105

Cladosporium C.cladosporioides 106,107

Colletotrichum C.gloeosporioides,C.coccodes 68,108

Mucor M.piriforms 109,110

Absidia Absidiaspp. 18,109

Rhizopus R.arrizhus 109,111

Macrophomina M.phaseolina 72

Bipolaris B.australiensis;B.hawaiiensis;B.spicifera 73,112

Fluconazoleisthemostprevalentclinicalantifungalusedto treatcryptococcosis.75_{However,thecontinueduseofthis}

anti-fungalisanincreasingconcernduetothefrequencyofisolates resistanttotriazolesusedinhumantherapeuticuse.76There isaneedforattentiontoazoleresistanceandoptimal ther-apyin regionswith high incidenceofcryptococcosis, such as the Asian-Pacific region (5.1–22.6%), Africa/Middle-East (7.0–33.3%),andEurope(4.2–7.1%).77_{Inadditiontofluconazole}

resistanceintheseregions,thenewpointofmutationinthe

ERG11geneofC.neoformansaffordedresistanceto voricona-zole(VRC).78_{Inthesecases,thespreadofisolatesexhibiting}

resistancetotriazolesintotheenvironmentandthosecapable ofcausinghumandiseasesmayaffecttheefficacyof therapeu-ticcontrolwithfungicidesofthesamegroup,especiallyinthe presenceofcross-resistance.79

ThemutagenesisinTR34/L98Hinazole-resistantAspergillus

mayhaveoriginatedduetotheuseoftriazolefungicidesin agroecosystems.14,28,80_{Suchmutationwasdetectedin89%of}

A.fumigatus-resistantisolatesfromairsamples,flowers,and soilsfromhospitalareas.6_{Microsatellitesequencingof}

clin-icaland environmentalisolatesthat leadtothe TR34/L98H

mutationrevealedhighgenetichomology,whichsuggestsa commonancestor.6,13

Futuredirections

Triazoleantifungalslargelyusedinplantprotectionarealso importantas antifungaltreatments inthe human medical fieldeventhoughtheypossessingstructuraldifferences. How-ever,sensitivepopulationsthatco-inhabitenvironmentsmay bereducedbytheselectionofisolatesresistanttofungicides. Fungiarisingfromagriculturalecosystemsasopportunistic pathogensmaycarrycross-resistancetotriazolesusedinthe medicalfield.Therestrictednumberofantifungalagentsfor clinicaluse,whichcontrastswiththelargenumberof agricul-turalfungicideswithsimilarmodesofaction,maybearisk factorthatlimitsthesuccessofthetherapeuticuseofthese drugs.

Currently, genome-wide studies, together with novel T-cell-based therapeutic approaches forthe prophylaxis and treatmentofopportunisticfungalinfections,havepromising avenuesofresearchinthedetectionofpotentiallynew anti-fungal targets.81,82 _{Thus, differentstrategies should bethe}

maingoalsofthepharmaceuticalindustry.

Giventhatthesearchfornewantifungaldrugsisalengthy process, the combination of drugs to achieve synergistic effectsiscurrentlyadoptedasanalternative.Thisapproach includesthecombinationofdrugswithdistinctmechanisms ofactionthatmayenhanceefficacybycombininglow concen-trationsofbothantifungalagents,thusdiminishingtherisk ofdevelopingresistance.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgments

The authors are thankful to the Coordenac¸ão de Aperfeic¸oamento de Pessoal de nível superior – CAPES forfinancialsupport.A.M.FuentefriaandH.S.Schrekkerare gratefultoCNPqforthePQfellowships.

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