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  3. A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens

A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens

  • Nat Microbiol. 2024 Apr 8. doi: 10.1038/s41564-024-01662-5.
Min Zhou # 1 2,  Longqiang Liu # 2,  Zihao Cong 2,  Weinan Jiang 2,  Ximian Xiao 2,  Jiayang Xie 2,  Zhengjie Luo 2,  Sheng Chen 2,  Yueming Wu 2,  Xinying Xue 3 4,  Ning Shao 2,  Runhui Liu 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
  • 2 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China.
  • 3 Department of Respiratory and Critical Care, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
  • 4 School of Clinical Medicine, Shandong Second Medical University, Weifang, China.
  • 5 State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China. rliu@ecust.edu.cn.
  • 6 Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Key Laboratory for Ultrafine Materials of Ministry of Education, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China. rliu@ecust.edu.cn.
  • # Contributed equally.
PMID: 38589468 DOI: 10.1038/s41564-024-01662-5
Abstract

Drug-resistant Fungal infections pose a significant threat to human health. Dual-targeting compounds, which have multiple targets on a single pathogen, offer an effective approach to combat drug-resistant pathogens, although ensuring potent activity and high selectivity remains a challenge. Here we propose a dual-targeting strategy for designing Antifungal compounds. We incorporate DNA-binding naphthalene groups as the hydrophobic moieties into the host defence peptide-mimicking poly(2-oxazoline)s. This resulted in a compound, (Gly0.8Nap0.2)20, which targets both the Fungal membrane and DNA. This compound kills clinical strains of multidrug-resistant fungi including Candida spp., Cryptococcus neoformans, Cryptococcus gattii and Aspergillus fumigatus. (Gly0.8Nap0.2)20 shows superior performance compared with amphotericin B by showing not only potent Antifungal activities but also high Antifungal selectivity. The compound also does not induce antimicrobial resistance. Moreover, (Gly0.8Nap0.2)20 exhibits promising in vivo therapeutic activities against drug-resistant Candida albicans in mouse models of skin abrasion, corneal Infection and systemic Infection. This study shows that dual-targeting Antifungal compounds may be effective in combating drug-resistant Fungal pathogens and mitigating Fungal resistance.

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