Alkylating Zoledronate Improves Its Antifungal Activity Against Multiply Drug-Resistant Candida auris

Alkylating zoledronate improves its antifungal activity against multiply drug-resistant Candida auris

Aidan Kane1*, Thanh Thi Hue Dinh2, Amy Cain2, Jane Hanrahan3 and Dee Carter1

1School of Life and Environmental Science, University of Sydney

2School of Natural Sciences, Macquarie University

3School of Pharmacy, University of Sydney

*Email: aidan.kane@sydney.edu.au

Candida auris is an emerging fungal pathogen with a high mortality rate. There is an urgent need for new antifungal chemotherapies due to concerning rates of resistance to currently available drugs. Zoledronate (ZOL) is a bisphosphonate prescribed to manage low-bone density disorders, and we have recently demonstrated its antifungal properties against various fungal pathogens. Previous research has found that adding a ten-carbon alkyl tail to ZOL significantly increases its antiparasitic activity. Fifteen clinical C. auris isolates were tested for susceptibility to three antifungals (fluconazole, caspofungin and amphotericin B), ZOL and its alkylated analogue (10-ZOL). Synergy between antifungals and bisphosphonates was assessed by fractional inhibitory concentration index (FICI). Inhibition of C. auris biofilms was measured with a colorimetric viability assay, and in vivo antifungal efficacy was assessed with a Galleria mellonella model of infection. While zoledronate was slightly antifungal (GM MIC100 = 332 mg/L), 10-ZOLwas substantially more inhibitory (GM MIC100 = 1.83). Fluconazole interacted synergistically with ZOL (mean FICI = 0.27; range 0.10–0.44) and 10-ZOL (mean FICI = 0.45; range 0.29–0.58), while amphotericin B had limited synergy with ZOL (mean FICI = 0.64; range 0.52–1.00), and 10-ZOL (mean FICI = 0.68; range 0.50–1.00). Biofilm viability was reduced for ten strains of C. auris by 10-ZOL, which was also able to significantly abrogate C. auris infection in vivo. We conclude that 10-ZOL is a promising therapeutic lead for the treatment of problematic strains of C. auris.