Mutation of G234 amino acid residue inCandida albicansdrug-resistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport

Abstract

(2015) Mutation of G234 amino acid residue in Candidaalbicans drugresistance-related protein Rta2p is associated with fluconazole resistance and dihydrosphingosine transport, Virulence, 6:6, 599-607, DOI: 10.1080/21505594.2015 Widespread and repeated use of azoles has led to the rapid development of drug resistance in Candida albicans. Our previous study found Rta2p, a membrane protein with 7 transmembrane domains, was involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Conserved amino acids in the transmembrane domain of Rta2p were subjected to site-directed mutagenesis. The sensitivity of C. albicans to fluconazole in vitro was examined by minimum inhibitory concentration and killing assay, and the therapeutic efficacy of fluconazole in vivo was performed by systemic mice candidiasis model. Furthermore, dihydrosphingosine transport activity was detected by NBD labeled D-erythro-dihydrosphingosine uptake and release assay, and the sensitivity to sphingolipid biosynthesis inhibitors. We successfully constructed 14 mutant strains of Rta2p, screened them by minimum inhibitory concentration and found Ca 2C did not completely induce fluconazole resistance with G158E and G234S mutations. Furthermore, we confirmed that G234S mutant enhanced the therapeutic efficacy of fluconazole against systemic candidiasis and significantly increased the accumulation of dihydrosphingosine by decreasing its release. However, G158E mutant didn't affect drug therapeutic efficacy in vivo and dihydrosphingosine transport in C. albicans. G234 of Rta2p in C. albicans is crucial in calcineurin-mediated fluconazole resistance and dihydrosphingosine transport.

Sphingolipidomics of drug resistant Candida auris clinical isolates reveal distinct sphingolipid species signatures

“…Notably, DHS levels were also reported to be significantly higher in CRS-MIS (caspofungin reduced susceptibility - micafungin increased susceptibility) mutants in A. nidulans and C. albicans [ 41 ]. DHS transport mediated by RTA2 was shown to be linked with FLC resistance in C. albicans [ 42 ]. Together, these studies suggest that DHS levels; influence drug susceptibilities in pathogenic fungi [ 41 ].…”

A pre-therapeutic coating for medical devices that prevents the attachment of Candida albicans

“…In fact, fluconazole-resistant Candida strains were more frequently reported [ 27 ] and with it the fear of a new threat. The Center for Disease Control (CDC) recently declared drug-resistant C. albicans as a major public health threat [ 13 – 16 , 54 ]. With the Pharmaceutical industry reporting a low inventory of antimicrobials [ 55 ], the search for non-traditional methods to prevent and manage nosocomial fungal infections is becoming more important than ever.…”

“…Among the commercially available antifungals, azoles, polyenes and echinocandins are the most effective [ 12 ]. In the last few years strains resistant to fluconazole have been reported, and with it a new threat to public health [ 13 – 16 ]. Therefore, new methods to prevent hospital-acquired infections by this opportunistic fungus are becoming more important than ever.…”

Single nucleotide polymorphisms and chromosomal copy number variation may impact the Sporothrix brasiliensis antifungal susceptibility and sporotrichosis clinical outcomes

“…We selected 28 genes with SNPs that are known to be important for antifungal resistance phenotype in human pathogenic fungi such as Candida albicans (Chen et al, 2019;Feng et al, 2020;Feng et al, 2017;Ramirez-Zavala et al, 2018;Whaley et al, 2016;Zhang et al, 2015a), C. tropicalis (Tan et al, 2015), C. glabrata (Ahmad et al, 2019;Arastehfar et al, 2019;Culakova et al, 2015;Delliere et al, 2016;Hou et al, 2019;Whaley et al, 2018), C. parapsilosis (Rybak et al, 2017), C. dubliniensis (Asadzadeh et al, 2017), Saccharomyces cerevisiae (Chen et al, 2014), Cryptococcus spp. (Billmyre et al, 2020;Son et al, 2018), Aspergillus spp.…”