A plant peptide with dual activity against multidrug-resistant bacterial and fungal pathogens

Multidrug-resistant (MDR) bacteria pose a significant threat to public health, and new sources of antibacterial candidates are urgently needed. Non-canonical peptides (NCPs), derived from non-canonical small open reading frames, represent small biological molecules with important roles in biology. However, antibacterial activity of NCPs remains largely unknown. Here, we discovered a plant-derived non-canonical antibacterial peptide (NCBP1) against both Gram-positive and Gram-negative bacteria. NCBP1 is composed of 11 amino acid residues with cationic surface potential and favorable safety and stability. Mechanistic studies revealed that NCBP1 displayed antibacterial activity by targeting phosphatidylglycerol and cardiolipin in bacterial membrane, resulting in membrane damage and dysfunction. Notably, NCBP1 showed promising efficacy in mice. Furthermore, NCBP1 effectively inhibited the growth of plant fungal pathogens and enhanced disease resistance in maize. Our results demonstrate the unexplored antimicrobial potential of plant-derived NCPs and provide an accessible source for the discovery of antimicrobial substances against MDR and fungal pathogens.