title: Cross-resistance to fluconazole induced by exposure to the agricultural azole tetraconazole: an environmental resistance school?
abstract: This study aimed to investigate the influence of tetraconazole and malathion, both used in agricultural activities, on resistance to fluconazole, itraconazole and voriconazole in Candida parapsilosis ATCC 22019. The susceptibility to tetraconazole, malathion, fluconazole, itraconazole and voriconazole, through broth microdilution. Then, 12 independent replicates, were separated and exposed to four treatment groups, each one containing three replicates: G1: tetraconazole; G2: malathion; G3: fluconazole (positive control); G4: negative control. Replicates from G1, G2 and G3, were exposed to weekly increasing concentrations of tetraconazole, malathion and fluconazole, respectively, ranging from MIC/2 to 32 × MIC, throughout 7 weeks. The exposure to tetraconazole, but not malathion, decreased susceptibility to clinical azoles, especially fluconazole. The tetraconazole-induced fluconazole resistance is partially mediated by the increased activity of ATP-dependent efflux pumps, considering the increase in antifungal susceptibility after the addition of the efflux pump inhibitor, promethazine, and the increase in rhodamine 6G efflux and CDR gene expression in the G1 replicates. Moreover, MDR expression was only detected in G1 and G3 replicates, suggesting that MDR pumps are also involved in tetraconazole-induced fluconazole resistance. It is noteworthy that tetraconazole and fluconazole-treated replicates behaved similarly, therefore, resistance to azoles of clinical use may be a consequence of using azoles in farming activities.
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.|School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: Marcos Fábio Gadelha
authors: MF
authors: Rocha
authors: School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: L P
authors: LP
authors: Alencar
authors: School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: M A N
authors: MA
authors: Paiva
authors: School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: Luciana Magalhães
authors: LM
authors: Melo
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: Silviane Praciano
authors: SP
authors: Bandeira
authors: School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: Y B
authors: YB
authors: Ponte
authors: School of Veterinary Medicine, Postgraduate Program in Veterinary Sciences, State University of Ceará, Fortaleza, Ceará, Brazil.
authors: Jamille Alencar
authors: JA
authors: Sales
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: G M M
authors: GM
authors: Guedes
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: D S C M
authors: DS
authors: Castelo-Branco
authors: School of Medicine, Christus College - Unichristus, Fortaleza, Ceará, Brazil.
authors: T J P G
authors: TJ
authors: Bandeira
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: R A
authors: RA
authors: Cordeiro
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: W A
authors: WA
authors: Pereira-Neto
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: G S
authors: GS
authors: Brandine
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: José Luciano Bezerra
authors: JL
authors: Moreira
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: José Júlio Costa
authors: JJ
authors: Sidrim
authors: Department of Pathology and Legal Medicine, Postgraduate Program in Medical Microbiology, Specialized Medical Mycology Center, Federal University of Ceará, Fortaleza, Ceará, Brazil.
authors: Raimunda Sâmia Nogueira
authors: RS
authors: Brilhante
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects* / Q000235:genetics; D002722:Chlorobenzenes / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004875:Ergosterol / Q000032:analysis; D015725:Fluconazole / Q000494:pharmacology*; D005659:Fungicides, Industrial / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology; D008294:Malathion / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011398:Promethazine / Q000494:pharmacology; D012235:Rhodamines; D058886:Sterol 14-Demethylase / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*; D065819:Voriconazole / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D018528:ATP-Binding Cassette Transporters; D018926:Anti-Allergic Agents; D000935:Antifungal Agents; D002722:Chlorobenzenes; D004875:Ergosterol; D015725:Fluconazole; D005659:Fungicides, Industrial; D017964:Itraconazole; D008294:Malathion; D011398:Promethazine; D012235:Rhodamines; D058886:Sterol 14-Demethylase; D014230:Triazoles; D065819:Voriconazole; C072232:rhodamine 3G; C524826:tetraconazole; D005466:Fluorocarbons
keywords: CDR genes; Candida sp.; azole resistance; efflux pumps; environmental resistance; tetraconazole