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Significance New antibacterial strategies that circumvent existing mechanisms hold promise in the fight against drug-resistant bacteria. Here we present an antibacterial mechanism that safeguards cells and animals by shutting down an intracellular signal through a site-selective covalent peptide-protein reaction instead of acting on bacterium cells. The novelty of this work is multifold, including a cysteine- specific reaction at an SH3 domain of an adaptor protein in cells, selective blockage of the second SH3 domain of Nck but not the other two SH3 domains, and prevention of EPEC-induced infection in animals for at least 12 h by reactive peptide. Thus, this preventative mechanism differs significantly from the bactericidal actions of antibiotics.

Safeguarding intestine cells against enteropathogenic Escherichia coli by intracellular protein reaction, a preventive antibacterial mechanism