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

• Published in: FEMS microbiology letters Vol. 362; no. 22; p. fnv188
• Main Authors: Singh, Ravindra Pal, Okubo, Ken-ichi, Ohtani, Kaori, Adachi, Keika, Sonomoto, Kenji, Nakayama, Jiro
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.11.2015
• Subjects: Alanine; Bacteria; Clostridium perfringens; Clostridium perfringens - drug effects; Clostridium perfringens - physiology; DNA Mutational Analysis; Gene expression; Gene Expression Regulation, Bacterial - drug effects; Inhibitory Concentration 50; Microbiology; Mutagenesis; Peptides; Peptides - genetics; Peptides - metabolism; Perfluorooctanoic acid; Quorum Sensing; Signal transduction; Signal Transduction - drug effects; Structure-Activity Relationship; Thiolactone; Toxins; Transcription; Transduction; Virulence Factors - biosynthesis; synthetic AIP; quorum sensing; quorum-sensing inhibitor; toxin gene; analogous; Clostridium perfringens; synthetic AIPCp analogous
• ISSN: 1574-6968; 0378-1097; 1574-6968
• DOI: 10.1093/femsle/fnv188

In Clostridium perfringens, a 5-membered thiolactone peptide acts as an autoinducing peptide (AIPCp) 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 AIPCp. Alanine scanning study of AIPCp 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-AIPCp-L2A/T5A (partial agonist) and Z-AIPCp-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. Based on the structure–activity relationship study on an autoinducing peptide (AIPCp), two different types of quorum-quenching peptides were developed, which inhibit the expression of perfringlysin gene (pfoA) in Clostridium perfringens.