Phylogenetic and syntenic analyses of the 12-spanner drug: H+ antiporter family 1 (DHA1) in pathogenic Candida species: Evolution of MDR1 and FLU1 genes

IBB – Institute for Biotechnology and Bioengineering, Centre for Biological and Chemical Engineering, Department of Bioengineering Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049–001 Lisboa, Portugal
Genomics (Impact Factor: 2.28). 07/2014; 104(1). DOI: 10.1016/j.ygeno.2014.05.005


Candida albicans and other pathogenic Candida species can develop resistance to clinical fungicides through active drug export mediated by multidrug efflux pumps, in particular by members of the drug:H+ antiporter family 1 (DHA1). The DHA1 proteins encoded in the genomes of 31 hemiascomycetous strains from 25 species were identified and homology relationships between these proteins and the functionally characterized DHA1 in the model yeast S. cerevisiae were established. Gene neighbourhood analysis allowed the reconstruction of sixteen DHA1 lineages conserved during the CTG complex species evolution. The evolutionary history of C. albicans MDR1 and FLU1 genes and C. dubliniensis, C. tropicalis and C. parapsilosis MDR1 genes was detailed. Candida genomes show an abundant number of MDR1 and FLU1 homologs but the chromosome environment where MDR1 homologs reside was poorly conserved during evolution. Gene duplication and loss are major mechanisms underlying the evolution of the DHA1 genes in Candida species.

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    • "(B) Circular cladogram showing the corresponding tree topology. The DHA1 proteins are distributed into 20 known phylogenetic clusters, labeled using letters and based on previous cluster annotation (Dias and Sá-Correia, in press), and 8 new phylogenetic clusters (clusters 1–4 and 6–7) comprising only members of the filamentous fungi. (C) Radial phylogram showing the amino acid sequence similarity distances between these 95 full-size DHA2 transporters. "
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    ABSTRACT: Infections caused by opportunistic fungal pathogens have reached concerning numbers due to the increase of the immunocrompromised human population and to the development of antifungal resistance. This resistance is often attributed to the action of multidrug efflux pumps, belonging to the ATP-binding cassette (ABC) superfamily and the major facilitator superfamily (MFS). Although many studies have focused on the role of ABC multidrug efflux transporters, little is still known on the part played by the Drug:H(+) Antiporter (DHA) family of the MFS in this context. This review summarizes current knowledge on the role in antifungal drug resistance, mode of action and phylogenetic relations of DHA transporters, from the model yeast S. cerevisiae to pathogenic yeasts and filamentous fungi. Through the compilation of the predicted DHA transporters in the medically relevant Candida albicans, C. glabrata, C. parapsilosis, C. lusitaniae, C. tropicalis, C. guilliermondii, Cryptococcus neoformans, and Aspergillus fumigatus species, the fact that only 5% of the DHA transporters from these organisms have been characterized so far is evidenced. The role of these transporters in antifungal drug resistance and in pathogen-host interaction is described and their clinical relevance discussed. Given the knowledge gathered for these few DHA transporters, the need to carry out a systematic characterization of the DHA multidrug efflux pumps in fungal pathogens, with emphasis on their clinical relevance, is highlighted.
    Frontiers in Physiology 05/2014; 5:197. DOI:10.3389/fphys.2014.00197 · 3.53 Impact Factor