Feature-Based Molecular Networking Guided Characterization of Clonocoprogen Siderophores with Anti-Pseudomonas aeruginosa Activity in Nematodes through Immune Up-Regulating Effects.

Abstract

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 Clonostachys rosea 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 Caenorhabditis elegans exposed to Pseudomonas aeruginosa, with EC₅₀ 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 P. aeruginosa. 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.