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Fusarium keratoplasticum  is arguably the most common  Fusarium solani  species complex (FSSC) species associated with human infections. Invasive fusariosis is a life-threatening fungal infection that is difficult to treat with conventional azole antifungals. Azole drug resistance is often caused by the increased expression of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters of the ABCG sub-family. Most investigations of  Fusarium  ABC transporters associated with azole antifungal drug resistance are limited to plant pathogens. Through the manual curation of the entire ABCG protein family of four FSSC species including the fully annotated genome of the plant pathogen  Nectria haematococca  we identified PDR transporters  ABC1  and  ABC2  as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of  Fusarium keratoplasticum . An initial investigation of the transcriptional response of logarithmic phase  F. keratoplasticum  cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of  ABC1  while  ABC2  mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of  F. keratoplasticum ABC1  and  ABC2  in the genetically modified  Saccharomyces cerevisiae  host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although  ABC1  and  ABC2  were only moderately (20% and 10%, respectively) expressed compared to the  Candida albicans  multidrug efflux pump  CDR1 , overexpression of  F. keratoplasticum ABC1  caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than  CDR1 . Our investigations suggest an important role for  ABC1  orthologues in the innate azole resistance phenotype of FSSC species.

PDR Transporter ABC1 Is Involved in the Innate Azole Resistance of the Human Fungal Pathogen Fusarium keratoplasticum