Peptaibiotics: Harnessing the potential of microbial secondary metabolites for mitigation of plant pathogens

Agricultural systems are in need of low-cost, safe antibiotics to protect crops from pests and diseases. Peptaibiotics, a family of linear, membrane-active, amphipathic polypeptides, have been shown to exhibit antibacterial, antifungal, and antiviral activity, and to be inducers of plant resistance against a wide range of phytopathogens. Peptaibiotics belong to the new generation of alternatives to agrochemicals, aligned with the United Nations Sustainable Development Goals and the One Health approach toward ensuring global food security and safety. Despite that, these fungi-derived, non-ribosomal peptides remain surprisingly understudied, especially in agriculture, where only a small number has been tested against a reduced number of phytopathogens. This lack of adoption stems from peptaibiotics' poor water solubility and the difficulty to synthesize and purify them in vitro, which compromises their delivery and inclusion in formulations. In this review, we offer a comprehensive analysis of peptaibiotics' classification, biosynthesis, relevance to plant protection, and mode of action against phytopathogens, along with the techniques enabling researchers to extract, purify, and elucidate their structure, and the databases holding such valuable data. It is also discussed how chemical synthesis and ionic liquids could increase their solubility, how genetic engineering and epigenetics could boost in vitro production, and how omics can reduce screenings' workload through in silico selection of the best candidates. These strategies could turn peptaibiotics into effective, ultra-specific, biodegradable tools for phytopathogen control.