Rationale design of quorum-quenching peptides that target the VirSR system of Clostridium perfringens

In Clostridium perfringens, a 5-membered thiolactone peptide acts as an autoinducing peptide (AIP_Cp) to activate the VirSR two-component signal transduction system, which in turn controls the expression of genes encoding multiple toxins, including α, θ and κ. To develop anti-pathogenic agents against virulent C. perfringens, quorum-quenching peptides were rationally designed based on the structure-activity relationship (SAR) data on AIP_Cp. Alanine scanning study of AIP_Cp suggested that Trp³ and Phe⁴ are involved in receptor binding and activation, respectively. On the basis of the SAR, we designed two quorum-quenching peptides with different modes of action: Z-AIP_Cp-L2A/T5A (partial agonist) and Z-AIP_Cp-F4A/T5S (partial antagonist). Both peptides significantly attenuated transcription of θ toxin gene (pfoA) in a virulent strain of C. perfringens with IC₅₀ = 0.32 and 0.72 μM, respectively.