AUTHOR=James Jasper Elvin , Lamping Erwin , Santhanam Jacinta , Cannon Richard David 

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

JOURNAL=Frontiers in Microbiology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2021.673206

DOI=10.3389/fmicb.2021.673206

ISSN=1664-302X

ABSTRACT=<p><italic>Fusarium keratoplasticum</italic> is arguably the most common <italic>Fusarium solani</italic> 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 <italic>Fusarium</italic> 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 <italic>Nectria haematococca</italic> we identified PDR transporters <italic>ABC1</italic> and <italic>ABC2</italic> as the efflux pump candidates most likely to be associated with the innate azole resistance phenotype of <italic>Fusarium keratoplasticum</italic>. An initial investigation of the transcriptional response of logarithmic phase <italic>F. keratoplasticum</italic> cells to 16 mg/L voriconazole confirmed strong upregulation (372-fold) of <italic>ABC1</italic> while <italic>ABC2</italic> mRNA levels were unaffected by voriconazole exposure over a 4 h time-period. Overexpression of <italic>F. keratoplasticum ABC1</italic> and <italic>ABC2</italic> in the genetically modified <italic>Saccharomyces cerevisiae</italic> host ADΔΔ caused up to ∼1,024-fold increased resistance to a number of xenobiotics, including azole antifungals. Although <italic>ABC1</italic> and <italic>ABC2</italic> were only moderately (20% and 10%, respectively) expressed compared to the <italic>Candida albicans</italic> multidrug efflux pump <italic>CDR1</italic>, overexpression of <italic>F. keratoplasticum ABC1</italic> caused even higher resistance levels to certain xenobiotics (e.g., rhodamine 6G and nigericin) than <italic>CDR1</italic>. Our investigations suggest an important role for <italic>ABC1</italic> orthologues in the innate azole resistance phenotype of FSSC species.</p>