ABC Transporter Genes Show Upregulated Expression in Drug-Resistant Clinical Isolates of Candida auris: A Genome-Wide Characterization of ATP-Binding Cassette (ABC) Transporter Genes

Abstract

ATP-binding cassette (ABC) superfamily members have a key role as nutrient importers and exporters in bacteria. However, their role as drug exporters in eukaryotes brought this superfamily member to even greater prominence. The capacity of ABC transporters to efflux a broad spectrum of xenobiotics represents one of the major mechanisms of clinical multidrug resistance in pathogenic fungi including Candida species. Candida auris , a newly emerged multidrug-resistant fungal pathogen of humans, has been responsible for multiple outbreaks of drug-resistant infections in hospitals around the globe. Our study has analyzed the entire complement of ABC superfamily transporters to assess whether these play a major role in drug resistance mechanisms of C. auris . Our bioinformatics analyses identified 28 putative ABC proteins encoded in the genome of the C. auris type-strain CBS 10913T; 20 of which contain transmembrane domains (TMDs). Quantitative real-time PCR confirmed the expression of all 20 TMD transporters, underlining their potential in contributing to the C. auris drug-resistant phenotype. Changes in transcript levels after short-term exposure of drugs and in drug-resistant C. auris isolates suggested their importance in the drug resistance phenotype of this pathogen. CAUR_02725 orthologous to CDR1 , a major multidrug exporter in other yeasts, showed consistently higher expression in multidrug-resistant strains of C. auris . Homologs of other ABC transporter genes, such as CDR4 , CDR6 , and SNQ2 , also displayed raised expression in a sub-set of clinical isolates. Together, our analysis supports the involvement of these transporters in multidrug resistance in C. auris .

Nine Things Genomics Can Tell Us About Candida auris

“…Another one is located within a predicted transmembrane protein that could contribute to drug resistance (Escandón et al, 2019). Drug transporters overexpression upon administering amphotericin B was also observed by Wasi et al In their study, they found 8.7-fold increase in expression of a homolog of CDR6 ABC transporter (Wasi et al, 2019). In the search for more robust drugs and drug targets, we urgently need to better understand the structure and function of drug pumps in pathogenic fungi, as well as how allelic diversity and mutations can affect drug efficacy.…”

“…However, further work is required to understand how such polymorphisms may affect the functioning of the enzyme, which is responsible for the conversion of 5-fluorouracil into 5-fluoro-UMP acid monophosphate. For allylamines, a homolog of ABC transporter CDR6 was found to be significantly upregulated in drug-resistant C. auris following terbinafine treatment (Wasi et al, 2019).…”

“…The activity of azoles can be also reduced by decreasing the concentration of antifungals in the cell by means of efflux pumps. Recently, 20 ABC transporters that are putative efflux pumps have been identified in the C. auris genome, strain-type CBS 10913T (Wasi et al, 2019). Two drug transporters (CDR1 and MDR1) that have primarily been studied in C. albicans have orthologs in C. auris, and these orthologs are overexpressed in azole-resistant C. auris (Rybak et al, 2019).…”

Mutations in TAC1B : a Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris

“…Most notable of these is C. glabrata, in which nearly all of the clinical triazole resistance is attributable to overexpression of the ATP-binding cassette (ABC)type efflux pump-encoding genes C. glabrata CDR1 (CgCDR1), CgPDH1, and CgSNQ2 (16). The C. auris genome has recently been revealed to include a substantial number of efflux pump-encoding genes of both the ABC and major facilitator superfamily (MFS) classes, and triazole-resistant isolates of C. auris have been observed to exhibit efflux pump activity greatly exceeding (up to 14-fold higher) that of C. glabrata (17)(18)(19)).…”

Mutations in TAC1B: a novel genetic determinant of clinical fluconazole resistance in C. auris

“…(16) The C. auris genome has recently been revealed to encode a substantial number of efflux pump encoding genes of both the ABC and Major Facilitator Superfamily (MFS) classes, and triazole-resistant isolates of C. auris have been observed to exhibit efflux pump activity greatly exceeding (up to 14-fold higher) that of C. glabrata . (17-19) Furthermore, the increased expression of the C. auris ABC-type efflux pump-encoding gene, CDR1 , has previously been shown to substantially contribute to clinical triazole resistance. (20, 21) At present however, the genetic determinants underpinning the increased expression of efflux pump-encoding genes in C. auris remain unidentified.…”