Abstract
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.