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.
Highlights
Drug transporters are considered key determinants of drug activity by affecting absorption, distribution, and excretion of drugs in patients under treatment [1]
This review explores the scarce current knowledge regarding drug uptake in pathogenic fungi, and the clues that may be retrieved from the model yeast Saccharomyces cerevisiae and from human protozoa pathogens of the Leishmania and Trypanosoma genera
A tolerance of 10% is applied, meaning that alignments with a score almost identical to the best-hit are not lost. Following this bidirectional BLASTp analysis, the homolog proteins of human parasites in pathogenic fungi Candida albicans, Candida glabrata, Cryptococcus neoformans, and Aspergillus fumigatus were determined as follows: using the protein sequence of known parasite drug importers as the input for a BLASTp, best hits on the different fungal species were selected; using those best hits protein sequence as the input for a BLASTp, the best hit on the respective parasite proteome was determined; if it matches, those fungal hits were considered as homologs of the parasite transporter protein
Summary
Drug transporters are considered key determinants of drug activity by affecting absorption, distribution, and excretion of drugs in patients under treatment [1]. A tolerance of 10% is applied, meaning that alignments with a score almost identical to the best-hit are not lost Following this bidirectional BLASTp analysis, the homolog proteins of human parasites in pathogenic fungi Candida albicans, Candida glabrata, Cryptococcus neoformans, and Aspergillus fumigatus were determined as follows: using the protein sequence of known parasite drug importers as the input for a BLASTp, best hits on the different fungal species were selected; using those best hits protein sequence as the input for a BLASTp, the best hit on the respective parasite proteome was determined; if it matches, those fungal hits were considered as homologs of the parasite transporter protein. Evolutionary analyses were conducted in MEGA X (https://pubmed.ncbi.nlm.nih.gov/29722887/) [43]
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