2. Academic Validation
  3. New Generation Modified Azole Antifungals against Multidrug-Resistant Candida auris

New Generation Modified Azole Antifungals against Multidrug-Resistant Candida auris

  • J Med Chem. 2025 Jul 10;68(13):14054-14071. doi: 10.1021/acs.jmedchem.5c01253.
Yiyuan Chen 1,  Yunxiao Li 1,  Kazi S Nahar 1 2,  Md Mahbub Hasan 1 3,  Caleb Marsh 4,  Melanie Clifford 4,  Godwin A Aleku 1,  Steven L Kelly 5,  David C Lamb 5,  Chengetai Diana Mpamhanga 6,  Ilias Kounatidis 6,  Ajit J Shah 2,  Charlotte K Hind 4,  J Mark Sutton 1 4,  Khondaker Miraz Rahman 1
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Science, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
  • 2 Department of Natural Sciences, University of Middlesex, The Burroughs, Hendon, London NW4 4BT, United Kingdom.
  • 3 Department of Genetic Engineering and Biotechnology, Faculty of Biological Sciences, University of Chittagong, Chattogram 4331, Bangladesh.
  • 4 Countermeasures, Development, Evaluation and Preparedness, UK Health Security Agency, Manor Farm Road, Salisbury SP4 0JG, United Kingdom.
  • 5 Centre for Cytochrome P450 Biodiversity, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, SA2 8PP, United Kingdom.
  • 6 School of Life Health and Chemical Sciences, The Open University, Milton Keynes MK7 6AE, United Kingdom.
PMID: 40550788 DOI: 10.1021/acs.jmedchem.5c01253
Abstract

The rise of Antifungal resistance and limited treatment options highlight the urgent need for new drug classes. Candida auris is a serious global health threat with few effective therapies. In this study, novel azole-based compounds were developed by modifying the azole core with cyclic heteroaliphatic linkers connecting aromatic and heteroaromatic rings. Several compounds showed potent activity against C. auris, including azole-resistant strains, with MICs ranging from 0.016 to 4 μg/mL. The compounds also demonstrated strong activity against C. albicans, Nakaseomyces glabratus, C. tropicalis, and C. parapsilosis, with MICs mostly below 1 μg/mL. Compounds 7, 18, and 21 were more potent than fluconazole. Compound 7 inhibited CYP51, eradicated C. auris biofilms, and showed better intracellular accumulation than fluconazole. In vivo studies in Galleria mellonella and Drosophila melanogaster confirmed efficacy at 5 mg/kg and no toxicity up to 50 mg/kg, supporting further development of this scaffold against multidrug-resistant C. auris infections.

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