Abstract
The last decade has witnessed the rise of an extremely threatening healthcare-associated multidrug-resistant non-albicans Candida (NAC) species, Candida auris. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the major facilitator superfamily (MFS) of efflux pumps, drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against most of the tested substrates, the ortholog when overexpressed in a minimal background Saccharomyces cerevisiae strain, AD1-8u−, showed significant enhancement in the minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms.
Key points
• Fourteen putative DHA1 transporters are encoded in the Candida auris genome.
• Deletion of the CauMDR1 gene does not lead to major changes in drug resistance.
• CauMdr1 recognizes and effluxes numerous xenobiotics, including prominent azoles.
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Data availability
Data are available on request from the authors.
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Acknowledgements
The authors acknowledge the Central Instrument Research Facility at Amity University Haryana for confocal and flow cytometry facilities. AB would like to acknowledge funding support from SERB, Government of India, through the grant SRG/2019/000514. RK acknowledges JRF fellowship from SERB through the project SRG/2019/000514. SS acknowledges fellowship support from the ICMR, Government of India, in the form of an SRF award.
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This study is supported by funding from the Department of Biotechnology, Government of India to AB, RP, and AML through grant no. BT/PR32349/MED/29/1456/2019.
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Conceptualization: AB. Methodology: RK, SS, PV, AS, PA, and AB. Formal analysis and investigation: RK, SS, AML, RP, AP, and AB. Writing—original draft preparation: AB and RK. Writing—review and editing: RK, PV, AML, AP, and AB. Funding acquisition: AB, AML, and RP. Resources: AB. Supervision: AB.
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Khatoon, R., Sharma, S., Vishwakarma, P. et al. Genomic landscape of the DHA1 family in Candida auris and mapping substrate repertoire of CauMdr1. Appl Microbiol Biotechnol 106, 7085–7097 (2022). https://doi.org/10.1007/s00253-022-12189-2
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DOI: https://doi.org/10.1007/s00253-022-12189-2