title: Differential expression of ATP-binding cassette and/or major facilitator superfamily class efflux pumps contributes to voriconazole resistance in Aspergillus flavus.
abstract: Invasive aspergillosis remains a life-threatening infection in immunocompromised patients. Although clinical failures are attributed to poor host immunity, antifungal drug resistance may be a contributing factor. Reports of voriconazole (VRC) resistance (VRC-R) in clinical isolates of Aspergillus spp. continue to emerge from various centers around the world, and mechanisms contributing to drug resistance are poorly understood. The aim of this study is to study the role of multidrug resistance efflux pumps (MDR-EPs) in VRC-R in Aspergillus flavus using efflux pump inhibitors and quantitative reverse transcriptase polymerase chain reaction. Relative quantification of various MDR-EPs was performed pre-exposure and postexposure to VRC, which demonstrated an increase in 1 or more efflux pump gene transcripts to varying degrees in VRC-susceptible and VRC-R isolates of A. flavus. Exposure to sub-MIC of VRC causes up-regulation of genes encoding MDR-EPs, contributing to triazole resistance in A. flavus and may not be detected during routine antifungal susceptibility testing in vitro.
authors.affiliation: Wayne State University, Detroit, MI 48201; John D Dingell VA Medical Center, Detroit, MI 48201, USA. suganthini.krishnannatesan@va.gov
authors.forename: S Krishnan
authors.initials: SK
authors.lastname: Natesan
authors.forename: A K
authors.initials: AK
authors.lastname: Lamichchane
authors.forename: Subramanian
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000935:Antifungal Agents / Q000494:pharmacology; D001231:Aspergillus flavus / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000031:analogs & derivatives / Q000494:pharmacology; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics*; D005656:Fungal Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009840:Oligomycins / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D012331:RNA, Fungal / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D065819:Voriconazole
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000935:Antifungal Agents; D005656:Fungal Proteins; D009840:Oligomycins; D020033:Protein Isoforms; D011743:Pyrimidines; D012331:RNA, Fungal; D012333:RNA, Messenger; D014230:Triazoles; C031004:oligomycin A; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D065819:Voriconazole
keywords: Aspergillus flavus; Azole-resistance; CCCP; Efflux pumps; FICI; MDR; Oligomycina; Overexpression; Voriconazole; mRNA transcripts; qRT-PCR