Synthetic lipopeptides that interact with lipopolysaccharides are potent bactericidal compounds against Xylella fastidiosa

Novel strategies to control diseases caused by Xylella fastidiosa that affect important crops like grapevine, olive, almond, and citrus are necessary to prevent its establishment and spread in several countries. Target-oriented functional peptides toward the pathogen are potential new compounds, and peptides directed to lipopolysaccharides (LPS) are suitable candidates. In the present work, 36 peptides, including previously reported sequences and newly synthesized lipopeptides, were studied for their bactericidal and LPS neutralization activities, as well as for their hemolytic and phytotoxic activities. In a first stage, a simple and rapid method for detecting peptide-LPS interactions based on a chromogenic endotoxin assay was developed. A linear relationship was observed between LPS neutralization and the bactericidal activity. A strong LPS interaction was related to a high bactericidal activity, whereas peptides with slight or low interaction with LPS had low bactericidal activity. A selected group of lipopeptides that strongly interacted with the LPS was highly bactericidal with moderate-to-low hemolytic and phytotoxic activity ( BP389 , BP473 , and BP475 ). These lipopeptides incorporate a butanoyl group at the side chain of a lysine residue and an L- or D-phenylalanine at position 4. The interaction and cell lytic effect between BP473 and X. fastidiosa cells was confirmed by confocal microscopy experiments. These lipopeptides that target key components of the outer bacterial cell membrane are good candidates to mitigate infections by X. fastidiosa in plant hosts. IMPORTANCE Xylella fastidiosa is a gram-negative bacterium that affects crops of economic importance such as grapevine, olive, almond, and citrus. The lack of efficient methods to control the diseases caused by this pathogen prompts the research of novel strategies. Since lipopolysaccharides (LPS) are a major virulence factor of X. fastidiosa , the development of new compounds that target LPS constitutes a promising approach. We identified cationic lipopeptides with a strong LPS interaction, high bactericidal activity, and low toxicity. These lipopeptides can be considered good candidates to control X. fastidiosa infections.