Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling

Khandelwal, Nitesh; Chauhan, Neeraj; Sarkar, Parijat; Esquivel, Brooke D.; Coccetti, Paola; Singh, Ashutosh; Coste, Alix T.; Gupta, Meghna; Sanglard, Dominique; White, Theodore C.; Chauvel, Murielle; d’Enfert, Christophe; Chattopadhyay, Amitabha; Gaur, Naseem A.; Mondal, Alok K.; Prasad, Rajendra

doi:10.1074/jbc.m117.807032

Cited by 42 publications

(37 citation statements)

References 83 publications

(109 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…cerevisiae PDR12 with 85% sequence identity, which is involved in organic acid transport [ 64 ], while CAGL0I08019g with 36% sequence identity to CDR6/ROA1 of C . albicans governs resistance to azoles [ 65 ]. The half transporter CAGL0L07744g shows 67% sequence identity with S .…”

Section: Resultsmentioning

confidence: 99%

ABC transportome inventory of human pathogenic yeast Candida glabrata: Phylogenetic and expression analysis

et al. 2018

Self Cite

View full text Add to dashboard Cite

ATP-binding cassette (ABC) is one of the two major superfamilies of transporters present across the evolutionary scale. ABC superfamily members came to prominence due to their ability to extrude broad spectrum of substrates and to confer multi drug resistance (MDR). Overexpression of some ABC transporters in clinical isolates of Candida species was attributed to the development of MDR phenotypes. Among Candida species, Candida glabrata is an emerging drug resistant species in human fungal infections. A comprehensive analysis of such proteins in C. glabrata is required to untangle their role not only in MDR but also in other biological processes. Bioinformatic analysis of proteins encoded by genome of human pathogenic yeast C. glabrata identified 25 putative ABC protein coding genes. On the basis of phylogenetic analysis, domain organization and nomenclature adopted by the Human Genome Organization (HUGO) scheme, these proteins were categorized into six subfamilies such as Pleiotropic Drug Resistance (PDR)/ABCG, Multi Drug Resistance (MDR)/ABCB, Multi Drug Resistance associated Protein (MRP)/ABCC, Adrenoleukodystrophy protein (ALDp)/ABCD, RNase L Inhibitor (RLI)/ABCE and Elongation Factor 3 (EF3)/ABCF. Among these, only 18 ABC proteins contained transmembrane domains (TMDs) and were grouped as membrane proteins, predominantly belonging to PDR, MDR, MRP, and ALDp subfamilies. A comparative phylogenetic analysis of these ABC proteins with other yeast species revealed their orthologous relationship and pointed towards their conserved functions. Quantitative real time PCR (qRT-PCR) analysis of putative membrane localized ABC protein encoding genes of C. glabrata confirmed their basal expression and showed variable transcriptional response towards antimycotic drugs. This study presents first comprehensive overview of ABC superfamily proteins of a human fungal pathogen C. glabrata, which is expected to provide an important platform for in depth analysis of their physiological relevance in cellular processes and drug resistance.

show abstract

Section: Resultsmentioning

confidence: 99%

ABC transportome inventory of human pathogenic yeast Candida glabrata: Phylogenetic and expression analysis

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, some MDR transporters have been shown to influence the lipid composition of the plasma membrane, by promoting the transport of phospholipids and/or ergosterol, which thereby may affect the diffusion rate of the drugs across the membrane, [74]. It was recently shown that deletion of the poorly characterized C. albicans ABC transporter CaRoa1 results in increased membrane rigidity and, consequently, in a reduced intracellular concentration of azoles [75]. Further studies in Candida spp.…”

Section: Azolesmentioning

confidence: 99%

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

Salazar

Simões

Pedro

et al. 2020

JoF

View full text Add to dashboard Cite

Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies.

show abstract

“…(iv) Agar drug diffusion assay. The assay was performed using S. cerevisiae cells (1 ϫ 10 5 cells/ml), as described previously (51). Images were captured with a Bio-Rad ChemiDoc XRSϩ system, and the diameters of the zones of inhibition were measured using the quantification tool.…”

Section: Construction Of Site-directed Mutantsmentioning

confidence: 99%

Vacuolar Sequestration of Azoles, a Novel Strategy of Azole Antifungal Resistance Conserved across Pathogenic and Nonpathogenic Yeast

Khandelwal

Wasi

Nair

et al. 2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

Target alteration and overproduction and drug efflux through overexpression of multidrug transporters localized in the plasma membrane represent the conventional mechanisms of azole antifungal resistance. Here, we identify a novel conserved mechanism of azole resistance not only in the budding yeast Saccharomyces cerevisiae but also in the pathogenic yeast Candida albicans. We observed that the vacuolar-membrane-localized, multidrug resistance protein (MRP) subfamily, ATP-binding cassette (ABC) transporter of S. cerevisiae, Ybt1, could import azoles into vacuoles. Interestingly, the Ybt1 homologue in C. albicans, Mlt1p, could also fulfill this function. Evidence that the process is energy dependent comes from the finding that a Mlt1p mutant version made by converting a critical lysine residue in the Walker A motif of nucleotide-binding domain 1 (required for ATP hydrolysis) to alanine (K710A) was not able to transport azoles. Additionally, we have shown that, as for other eukaryotic MRP subfamily members, deletion of the conserved phenylalanine amino acid at position 765 (F765Δ) results in mislocalization of the Mlt1 protein; this mislocalized protein was devoid of the azole-resistant attribute. This finding suggests that the presence of this protein on vacuolar membranes is an important factor in azole resistance. Further, we report the importance of conserved residues, because conversion of two serines (positions 973 and 976, in the regulatory domain and in the casein kinase I [CKI] consensus sequence, respectively) to alanine severely affected the drug resistance. Hence, the present study reveals vacuolar sequestration of azoles by the ABC transporter Ybt1 and its homologue Mlt1 as an alternative strategy to circumvent drug toxicity among pathogenic and nonpathogenic yeasts.

show abstract

Azole resistance in a Candida albicans mutant lacking the ABC transporter CDR6/ROA1 depends on TOR signaling

Cited by 42 publications

References 83 publications

ABC transportome inventory of human pathogenic yeast Candida glabrata: Phylogenetic and expression analysis

ABC transportome inventory of human pathogenic yeast Candida glabrata: Phylogenetic and expression analysis

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

Vacuolar Sequestration of Azoles, a Novel Strategy of Azole Antifungal Resistance Conserved across Pathogenic and Nonpathogenic Yeast

Contact Info

Product

Resources

About