SRA

Multidrug-resistant (MDR) bacteria pose a significant threat to public health, and new sources of antibacterial compounds are urgently needed. Non-canonical peptides (NCPs), derived from non-canonical open reading frames (ORFs), play versatile functions in physiological processes in multicellular organisms. However, the antibacterial activity of NCPs remains largely unknown. Here, we discovered a broad-spectrum non-canonical antibacterial peptide (NCBP1) against both Gram-positive and Gram-negative bacteria. NCBP1 is encoded by an intergenic ORF in the maize genome, consisting of 11 amino acid residues with high cationic surface potential and favorable safety and stability. Mechanistic studies revealed that NCBP1 exhibited antibacterial activities by binding to phosphatidylglycerol and cardiolipin in the cytoplasmic membrane, resulting in membrane damage and dysfunction. Notably, NCBP1 showed promising efficacy in mice using a skin infection model. Our results demonstrate the unexplored antibacterial potential of plant-derived NCPs and provide an accessible source for the discovery of novel antibacterial substances against MDR pathogens.