Cdr1 in Focus: a Personal Reflection on Multidrug Transporter Research

Overview

Journal FEMS Yeast Res

Publisher Oxford University Press

Date 2025 Jan 30

PMID 39883094

Authors

Rajendra Prasad

Affiliations

Soon will be listed here.

Abstract

Drug resistance mechanisms in human pathogenic Candida species are constantly evolving. Over time, these species have developed diverse strategies to counter the effects of various drug classes, making them a significant threat to human health. In addition to well-known mechanisms such as drug target modification, overexpression, and chromosome duplication, Candida species have also developed permeability barriers to antifungal drugs through reduced drug import or increased efflux. The genomes of Candida species contain a multitude of drug resistance genes, many of which encode membrane efflux transporters that actively expel drugs, preventing their toxic accumulation inside the cells and contributing to multidrug resistance. This brief personal retrospective piece for the "Thematic Issue on Celebrating 30 Years of Cdr1 Research: new trends in antifungal therapy and drug resistance" looks back as to how antifungal research has shifted focus since the identification of the first multidrug transporter gene, CDR1 (Candida Drug Resistance 1), leading to new insights into how reduced azole permeability across Candida cell membranes influences antifungal susceptibility.

References

Gaur N, Puri N, Karnani N, Mukhopadhyay G, Goswami S, Prasad R . Identification of a negative regulatory element which regulates basal transcription of a multidrug resistance gene CDR1 of Candida albicans. FEMS Yeast Res. 2004; 4(4-5):389-99. DOI: 10.1016/S1567-1356(03)00204-6. View

Peng Y, Lu Y, Sun H, Ma J, Li X, Han X . Cryo-EM structures of Candida albicans Cdr1 reveal azole-substrate recognition and inhibitor blocking mechanisms. Nat Commun. 2024; 15(1):7722. PMC: 11379888. DOI: 10.1038/s41467-024-52107-w. View

Shariq M, Dhamgaye S, Nair R, Goyal N, Jain V, Mukhopadhyay A . The global regulator Ncb2 escapes from the core promoter and impacts transcription in response to drug stress in Candida albicans. Sci Rep. 2017; 7:46084. PMC: 5382705. DOI: 10.1038/srep46084. View

Khandelwal N, Kaemmer P, Forster T, Singh A, Coste A, Andes D . Pleiotropic effects of the vacuolar ABC transporter MLT1 of Candida albicans on cell function and virulence. Biochem J. 2016; 473(11):1537-52. PMC: 4888455. DOI: 10.1042/BCJ20160024. View

Kumari S, Kumar M, Esquivel B, Wasi M, Pandey A, Khandelwal N . Unmasking of CgYor1-Dependent Azole Resistance Mediated by Target of Rapamycin (TOR) and Calcineurin Signaling in Candida glabrata. mBio. 2022; 13(1):e0354521. PMC: 8764518. DOI: 10.1128/mbio.03545-21. View

Banerjee A, Moreno A, Khan M, Nair R, Sharma S, Sen S . Cdr1p highlights the role of the non-hydrolytic ATP-binding site in driving drug translocation in asymmetric ABC pumps. Biochim Biophys Acta Biomembr. 2019; 1862(2):183131. DOI: 10.1016/j.bbamem.2019.183131. View

Leppert G, McDevitt R, Falco S, van Dyk T, Ficke M, Golin J . Cloning by gene amplification of two loci conferring multiple drug resistance in Saccharomyces. Genetics. 1990; 125(1):13-20. PMC: 1203995. DOI: 10.1093/genetics/125.1.13. View

Puri N, Krishnamurthy S, Habib S, Hasnain S, Goswami S, Prasad R . CDR1, a multidrug resistance gene from Candida albicans, contains multiple regulatory domains in its promoter and the distal AP-1 element mediates its induction by miconazole. FEMS Microbiol Lett. 1999; 180(2):213-9. DOI: 10.1111/j.1574-6968.1999.tb08798.x. View

Shukla S, Yadav V, Mukhopadhyay G, Prasad R . Ncb2 is involved in activated transcription of CDR1 in azole-resistant clinical isolates of Candida albicans. Eukaryot Cell. 2011; 10(10):1357-66. PMC: 3187062. DOI: 10.1128/EC.05041-11. View

10.

Manoharlal R, Gorantala J, Sharma M, Sanglard D, Prasad R . PAP1 [poly(A) polymerase 1] homozygosity and hyperadenylation are major determinants of increased mRNA stability of CDR1 in azole-resistant clinical isolates of Candida albicans. Microbiology (Reading). 2009; 156(Pt 2):313-326. DOI: 10.1099/mic.0.035154-0. View

11.

Balzi E, Wang M, Leterme S, Van Dyck L, Goffeau A . PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J Biol Chem. 1994; 269(3):2206-14. View

12.

Banerjee A, Pata J, Chaptal V, Boumendjel A, Falson P, Prasad R . Structure, function, and inhibition of catalytically asymmetric ABC transporters: Lessons from the PDR subfamily. Drug Resist Updat. 2023; 71:100992. DOI: 10.1016/j.drup.2023.100992. View

13.

Smriti , Krishnamurthy S, Dixit B, Gupta C, Milewski S, Prasad R . ABC transporters Cdr1p, Cdr2p and Cdr3p of a human pathogen Candida albicans are general phospholipid translocators. Yeast. 2002; 19(4):303-18. DOI: 10.1002/yea.818. View

14.

Pasrija R, Panwar S, Prasad R . Multidrug transporters CaCdr1p and CaMdr1p of Candida albicans display different lipid specificities: both ergosterol and sphingolipids are essential for targeting of CaCdr1p to membrane rafts. Antimicrob Agents Chemother. 2007; 52(2):694-704. PMC: 2224756. DOI: 10.1128/AAC.00861-07. View

15.

Gaur M, Choudhury D, Prasad R . Complete inventory of ABC proteins in human pathogenic yeast, Candida albicans. J Mol Microbiol Biotechnol. 2005; 9(1):3-15. DOI: 10.1159/000088141. View

16.

Balan I, Alarco A, Raymond M . The Candida albicans CDR3 gene codes for an opaque-phase ABC transporter. J Bacteriol. 1997; 179(23):7210-8. PMC: 179668. DOI: 10.1128/jb.179.23.7210-7218.1997. View

17.

Ibe C, Pohl C . Update on the structure and function of Candida albicans drug efflux protein, Cdr1. Fungal Genet Biol. 2024; 175:103938. DOI: 10.1016/j.fgb.2024.103938. View

18.

Baghel P, Rawal M, Khan M, Sen S, Siddiqui M, Chaptal V . Multidrug ABC transporter Cdr1 of Candida albicans harbors specific and overlapping binding sites for human steroid hormones transport. Biochim Biophys Acta Biomembr. 2017; 1859(10):1778-1789. DOI: 10.1016/j.bbamem.2017.05.011. View

19.

Franz R, Michel S, Morschhauser J . A fourth gene from the Candida albicans CDR family of ABC transporters. Gene. 1998; 220(1-2):91-8. DOI: 10.1016/s0378-1119(98)00412-0. View

20.

Sanglard D, Ischer F, Monod M, Bille J . Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. Microbiology (Reading). 1997; 143 ( Pt 2):405-416. DOI: 10.1099/00221287-143-2-405. View