Multidrug-Resistant Transporter Mdr1p-Mediated Uptake of a Novel Antifungal Compound

Abstract

ABSTRACTThe activity of many anti-infectious drugs has been compromised by the evolution of multidrug-resistant (MDR) pathogens. For life-threatening fungal infections, such as those caused byCandida albicans, overexpression ofMDR1, which encodes an MDR efflux pump of the major facilitator superfamily (MFS), often confers resistance to chemically unrelated substances, including the most commonly used azole antifungals. As the development of new and efficacious antifungals has lagged far behind the growing emergence of resistant strains, it is imperative to develop strategies to overcome multidrug resistance. Previous advances have been mainly to deploy combinational therapy to restore azole susceptibility, which, however, requires coordination of two or more compounds. We observed a unique phenotype in which Mdr1p facilitates the uptake of a specific class of compounds. Among them, we describe a novel antifungal small molecule, bis[1,6-a:5′,6′-g]quinolizinium 8-methyl-salt (BQM) (U.S. patent application no. 61/793,090,2013), that has potent and broad antifungal activity. Notably, BQM exploits the MDR phenotype inC. albicansto promote the inhibitory effect. Rather than causing an antagonism of MDR strains, it exhibits a highly potentiated activity against a collection of clinical isolates and lab strains that overexpressMDR1. The activity of BQM againstMDR1-overexpressing isolates is due to its facilitated intracellular accumulation. Microarray comparisons showed an extensive upregulation ofMDR1as well as polyamine transporter genes in a fluconazole-resistant strain. We then demonstrated that the polyamine transporters augment the accumulation of BQM. Importantly, BQM had greater activity than fluconazole and itraconazole against various fungal pathogens, including MDRAspergillus fumigatus. Thus, our findings offer a paradigm shift to overcome MDR and the promise of improving antifungal treatment, especially in MDR pathogens.