Carrier-Mediated Drug Uptake in Fungal Pathogens

Abstract

Candida, Aspergillus, and Cryptococcus species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by the ability of fungal cells to develop drug resistance mechanisms. Drug effectiveness and drug resistance in human pathogens is very often affected by their “transportome”. Many studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ATP-Binding Cassette and Major Facilitator Superfamily. However, the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi. This review focuses on discussing current knowledge on drug uptake systems in fungal pathogens, highlighting the need for further studies on this topic of great importance. The following subjects are covered: (i) drugs imported by known transporter(s) in pathogenic fungi; and (ii) drugs imported by known transporter(s) in the model yeast Saccharomyces cerevisiae or in human parasites, aimed at the identification of their homologs in pathogenic fungi. Besides its contribution to increase the understanding of drug-pathogen interactions, the practical implications of identifying drug importers in human pathogens are discussed, particularly focusing on drug development strategies.

Inositol Phosphoryl Transferase, Ipt1, Is a Critical Determinant of Azole Resistance and Virulence Phenotypes in Candida glabrata

“…It is now well established that entry of azoles into Candida species and other pathogenic fungi is predominantly through facilitated diffusion. Increased antifungal drug uptake and accumulation by fungi could lead to increased drug susceptibility, while reduced drug accumulation could result in resistance to the drug [ 46 , 47 , 59 , 60 ]. We investigated whether increased FLC diffusion/accumulation could explain the increased fluconazole susceptibility of ΔCgipt1 cells.…”

Genomic evolution towards azole resistance in Candida glabrata clinical isolates unveils the importance of CgHxt4/6/7 in azole accumulation

“…Several studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ABC and MFS. Nonetheless, despite some efforts 25 , 34 , the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi 24 . Besides being an important mechanism of drug effectiveness acknowledged in human parasites 24 , decreased accumulation of drugs have been associated with azole resistance in Candida clinical isolates 25 .…”

“…Nonetheless, despite some efforts 25 , 34 , the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi 24 . Besides being an important mechanism of drug effectiveness acknowledged in human parasites 24 , decreased accumulation of drugs have been associated with azole resistance in Candida clinical isolates 25 . Nonetheless, the players underlying drug uptake have remained elusive for at least 20 years.…”

“…The putative hexose transporter CgHXT4/6/7 (ORF CAGL0A02233g ) stood out in the analysis, being hypothesized to work as an azole importer. Although little is known about how these drugs enter pathogenic fungal cells to exert their antifungal action 24 , it was demonstrated that azoles are imported by facilitated diffusion rather than passive diffusion or ATP-dependent import 25 . Moreover, fluconazole import differs among C. albicans resistant clinical isolates, which suggests that altered facilitated diffusion is possibly a previously uncharacterized mechanism of resistance to azole drugs 25 .…”

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

“…The outer membrane also contributes significantly to the permeability barrier in Gram-negatives (e.g., [ 265 , 434 , 443 , 444 , 448 , 458 , 459 , 460 , 461 , 462 , 463 , 464 , 465 , 466 ]). However, another specific area in which the role of transporters is largely unrecognised —albeit this is a specific subset of drug transport—pertains to the uptake transport of anti-infectives to their sites of action [ 439 , 467 ]. This can involve both the targets within the microbe and the host’s transporters when (as is common, e.g., [ 468 , 469 , 470 , 471 , 472 , 473 , 474 , 475 , 476 , 477 , 478 , 479 , 480 , 481 , 482 , 483 , 484 , 485 ]) the infective agents reside intracellularly.…”