Feature-Based Molecular Networking Guided Characterization of Clonocoprogen Siderophores with Anti-<i>Pseudomonas aeruginosa</i> Activity in Nematodes through Immune Up-Regulating Effects
Antibiotic resistance poses a severe threat to human health, necessitating research into antibiotics with unique mechanisms to combat drug resistance. Natural siderophores and their synthetic derivatives have become a promising resource for the development of anti-infectious agents. In this study, we introduce a new anti-infective agent with a mode of action that enhances host immunity without exerting direct antibacterial activity. We identified immune-activating clonocoprogen siderophores from the fungus <i>Clonostachys rosea</i> isolate CR15020 using an integrated approach, including genome mining, feature-based molecular networking (FBMN) and a nematode screening model. Although these siderophores displayed no inherent antibacterial properties, they significantly improved survival of <i>Caenorhabditis elegans</i> exposed to <i>Pseudomonas aeruginosa</i>, with EC<sub>50</sub> values ranging from 1.85 to 10.86 μM. This protection was achieved through up-regulation of the nematode's p38-MAPK and DAF/IGF immune pathways, as well as reducing the excretion of pyoverdine by <i>P. aeruginosa</i>. By leveraging immune modulation rather than direct bacterial inhibition, this approach offers a promising alternative to conventional antibiotics, addressing the urgent challenge of antibiotic resistance.
Authors
- Alex Tuffour
- Kangjie Lv
- Pengfei Yu (ORCID: https://orcid.org/0000-0002-3894-5697)
- Yi Jiang (ORCID: https://orcid.org/0000-0002-1847-252X)
- Guoliang Zhu (ORCID: https://orcid.org/0000-0002-6628-8874)
- Jingyu Zhang (ORCID: https://orcid.org/0000-0001-6668-2815)
- Xueting Liu (ORCID: https://orcid.org/0000-0002-1322-8253)
- Huimin Wu (ORCID: https://orcid.org/0000-0002-5522-3020)
- Tom Hsiang (ORCID: https://orcid.org/0000-0002-9549-1847)
- Huanqin Dai (ORCID: https://orcid.org/0000-0002-8108-815X)
- Frederick M. Ausubel (ORCID: https://orcid.org/0000-0002-6927-8460)
- Kun Wang (ORCID: https://orcid.org/0000-0003-2609-6058)
- Lixin Zhang (ORCID: https://orcid.org/0000-0003-0894-9520)
- Biao Ren (ORCID: https://orcid.org/0000-0003-4215-2873)
- Xinye Wang (ORCID: https://orcid.org/0000-0003-2095-6117)
- Weize Yuan
- Cheng‐Lin Jiang
Institutions
- Harvard University (US)
- East China University of Science and Technology (CN)
- Yunnan University (CN)
- Chinese Academy of Sciences (CN)
- Sichuan University (CN)
- Massachusetts General Hospital (US)
- National Clinical Research Center for Digestive Diseases (CN)
- Czech Academy of Sciences, Institute of Microbiology (CZ)
- State Key Laboratory of Oral Diseases
- State Key Laboratory of Bioreactor Engineering
- University of Guelph (CA)
Publication Details
- Journal
- ACS Chemical Biology
- Published
- 2025-06-22
- DOI
- https://doi.org/10.1021/acschembio.5c00178
- Primary Topic
- Piperaceae Chemical and Biological Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Science and Technology Commission of Shanghai Municipality
- State Key Laboratory of Bioreactor Engineering
- Higher Education Discipline Innovation Project
- National Key Research and Development Program of China