{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T13:13:20Z","timestamp":1793366000655,"version":"4.5.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T00:00:00Z","timestamp":1658966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Fungal Biol."],"abstract":"\n Fluconazole-resistant\n Candida parapsilosis<\/jats:italic>\n (FLZR-CP) outbreaks are a growing public health concern and have been reported in numerous countries. Patients infected with FLZR-CP isolates show fluconazole therapeutic failure and have a significantly increased mortality rate. Because fluconazole is the most widely used antifungal agent in most regions with outbreaks, it is paramount to restore its antifungal activity. Milbemycin oxim (MOX), a well-known canine endectocide, is a potent efflux pump inhibitor that significantly potentiates the activity of fluconazole against FLZR\n C<\/jats:italic>\n .\n glabrata<\/jats:italic>\n and\n C<\/jats:italic>\n .\n albicans.<\/jats:italic>\n However, the FLZ-MOX combination has not been tested against FLZR-CP isolates, nor is it known whether MOX may also potentiate the activity of echinocandins, a different class of antifungal drugs. Furthermore, the extent of involvement of efflux pumps\n CDR1<\/jats:italic>\n and\n MDR1<\/jats:italic>\n and ergosterol biosynthesis enzyme\n ERG11<\/jats:italic>\n and their link with gain-of-function (GOF) mutations in their transcription regulators (\n TAC1<\/jats:italic>\n ,\n MRR1<\/jats:italic>\n , and\n UPC2<\/jats:italic>\n ) are poorly characterized among FLZR-CP isolates. We analyzed 25 C.\n parapsilosis<\/jats:italic>\n isolates collected from outbreaks in Turkey and Brazil by determining the expression levels of\n CDR1<\/jats:italic>\n ,\n MDR1<\/jats:italic>\n , and\n ERG11<\/jats:italic>\n , examining the presence of potential GOF mutations in their transcriptional regulators, and assessing the antifungal activity of FLZ-MOX and micafungin-MOX against FLZR and multidrug-resistant (MDR)\n C<\/jats:italic>\n .\n parapsilosis<\/jats:italic>\n isolates.\n ERG11<\/jats:italic>\n was found to be universally induced by fluconazole in all isolates, while expression of\n MDR1<\/jats:italic>\n was unchanged. Whereas mutations in\n MRR1<\/jats:italic>\n and\n UPC2<\/jats:italic>\n were not detected,\n CDR1<\/jats:italic>\n was overexpressed in three Brazilian FLZR-CP isolates, which also carried a novel\n \n TAC1\n L518F<\/jats:sup>\n <\/jats:italic>\n mutation. Of these three isolates, one showed increased basal expression of\n CDR1<\/jats:italic>\n , while the other two overexpressed\n CDR1<\/jats:italic>\n only in the presence of fluconazole. Interestingly, MOX showed promising antifungal activity against FLZR isolates, reducing the FLZ MIC 8- to 32-fold. However, the MOX and micafungin combination did not exert activity against an MDR\n C<\/jats:italic>\n .\n parapsilosis<\/jats:italic>\n isolate. Collectively, our study documents that the mechanisms underpinning FLZR are region specific, where\n ERG11<\/jats:italic>\n mutations were the sole mechanism of FLZR in Turkish FLZR-CP isolates, while simultaneous overexpression of\n CDR1<\/jats:italic>\n was observed in some Brazilian counterparts. Moreover, MOX and fluconazole showed potent synergistic activity, while the MOX-micafungin combination showed no synergy.\n <\/jats:p>","DOI":"10.3389\/ffunb.2022.906681","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T11:21:06Z","timestamp":1659007266000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":10,"title":["Determinants of fluconazole resistance and the efficacy of fluconazole and milbemycin oxim combination against Candida parapsilosis clinical isolates from Brazil and Turkey"],"prefix":"10.3389","volume":"3","author":[{"given":"Farnaz","family":"Daneshnia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00fcleyha","family":"Hilmio\u011flu Polat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Macit","family":"Ilkit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Shor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Nobrega","family":"de Almeida J\u00fanior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larissa M.","family":"Favarello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaldo Lopes","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"Arastehfar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Perlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"382","DOI":"10.111\/myc.13053","article-title":"Epidemiological features of nosocomial candidaemia in neonates, infants and children: a multicentre study in Iran","volume":"63","author":"Ahangarkani","year":"2020","journal-title":"Mycoses"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e01001","DOI":"10.1128\/AAC.01001-20","article-title":"First report of candidemia clonal outbreak caused by emerging fluconazole-resistant Candida parapsilosis isolates harboring Y132F and\/or Y132F+K143R in Turkey","volume":"64","author":"Arastehfar","year":"2020","journal-title":"Antimicrob. 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