New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>

Chen, Yiyuan; Li, Yunxiao; Nahar, Kazi S.; Hasan, Md. Mahbub; Marsh, Caleb; Clifford, Melanie; Aleku, Godwin A.; Kelly, Steven; Lamb, David; Mpamhanga, Chengetai Diana; Kounatidis, Ilias; Shah, Ajit J.; Hind, Charlotte K.; Sutton, J. Mark; Rahman, Khondaker Miraz

doi:10.1021/acs.jmedchem.5c01253

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New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>

Yiyuan Chen, Yunxiao Li, Kazi S. Nahar, Md. Mahbub Hasan, Caleb Marsh

, Melanie Clifford, Godwin A. Aleku

, Steven Kelly, David Lamb

, Chengetai Diana Mpamhanga

, Ilias Kounatidis, Ajit J. Shah, Charlotte K. Hind

, J. Mark Sutton, Khondaker Miraz Rahman

Journal of Medicinal Chemistry, Volume: 68, Issue: 13, Pages: 14054 - 14071

Swansea University Authors: Steven Kelly, David Lamb

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DOI (Published version): 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 heteroalipha...

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Published in:	Journal of Medicinal Chemistry
ISSN:	0022-2623 1520-4804
Published:	American Chemical Society (ACS) 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa69875

first_indexed	2025-07-03T10:59:24Z
last_indexed	2025-08-02T05:01:04Z
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spelling	2025-08-01T14:47:13.3580037 v2 69875 2025-07-03 New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i> b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 1dc64e55c2c28d107ef7c3db984cccd2 0000-0001-5446-2997 David Lamb David Lamb true false 2025-07-03 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. Journal Article Journal of Medicinal Chemistry 68 13 14054 14071 American Chemical Society (ACS) 0022-2623 1520-4804 23 6 2025 2025-06-23 10.1021/acs.jmedchem.5c01253 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee Funding was received from the China Scholarship Council (CSC) and a Medical Research Council Confidence in Concept grant (award code MC_PC_13065). 2025-08-01T14:47:13.3580037 2025-07-03T11:51:45.5672244 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Yiyuan Chen 1 Yunxiao Li 2 Kazi S. Nahar 3 Md. Mahbub Hasan 4 Caleb Marsh 0000-0002-0265-0221 5 Melanie Clifford 6 Godwin A. Aleku 0000-0003-0969-5526 7 Steven Kelly 8 David Lamb 0000-0001-5446-2997 9 Chengetai Diana Mpamhanga 0000-0002-6897-259X 10 Ilias Kounatidis 11 Ajit J. Shah 12 Charlotte K. Hind 0000-0002-3763-3106 13 J. Mark Sutton 14 Khondaker Miraz Rahman 0000-0001-8566-8648 15 69875__34652__10dc1bf042094d80b0e9a84d0a113245.pdf 69875.VOR.pdf 2025-07-03T11:57:34.4837419 Output 3881490 application/pdf Version of Record true © 2025 The Authors. This article is licensed under CC-BY 4.0 . true eng https://creativecommons.org/licenses/by/4.0/
title	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
spellingShingle	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i> Steven Kelly David Lamb
title_short	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
title_full	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
title_fullStr	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
title_full_unstemmed	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
title_sort	New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>
author_id_str_mv	b17cebaf09b4d737b9378a3581e3de93 1dc64e55c2c28d107ef7c3db984cccd2
author_id_fullname_str_mv	b17cebaf09b4d737b9378a3581e3de93_*_Steven Kelly 1dc64e55c2c28d107ef7c3db984cccd2_*_David Lamb
author	Steven Kelly David Lamb
author2	Yiyuan Chen Yunxiao Li Kazi S. Nahar Md. Mahbub Hasan Caleb Marsh Melanie Clifford Godwin A. Aleku Steven Kelly David Lamb Chengetai Diana Mpamhanga Ilias Kounatidis Ajit J. Shah Charlotte K. Hind J. Mark Sutton Khondaker Miraz Rahman
format	Journal article
container_title	Journal of Medicinal Chemistry
container_volume	68
container_issue	13
container_start_page	14054
publishDate	2025
institution	Swansea University
issn	0022-2623 1520-4804
doi_str_mv	10.1021/acs.jmedchem.5c01253
publisher	American Chemical Society (ACS)
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description	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.
published_date	2025-06-23T05:29:49Z
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score	11.096007

New Generation Modified Azole Antifungals against Multidrug-Resistant <i>Candida auris</i>

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