Proteoliposome‐based model for screening inhibitors targeting histidine kinase AgrC

A proteoliposome‐based model for screening the inhibotors targeting histidine kinase AgrC was build, and two monomers, rhein and aloeemodin, were identified using this model as effective inhibitors among 14 kinds of traditional Chinese medicine monomers. The inhibitory effect of rhein and aloeemodin on the growth of the suspended bacteria was dose dependent, and subinhibitory concentrations of them can significantly reduce the expression of three virulence factors(hla, clfA and clpP) which are regulated by agr system.

Abstract

AgrC, as an integral membrane receptor protein with histidine kinase activity, is an important component of the agr quorum‐sensing system of Staphylococcus aureus. AgrC acts as a sensor for the recognition of environmental signals and transduction of the signals into the cytoplasm. Therefore, AgrC is considered to be a compelling target for the development of novel quorum sensing inhibitors. Here, we constructed a proteoliposome‐based model for screening inhibitors targeting AgrC by incorporating AgrC into liposomes. We demonstrated that the dissolution state of the liposome was a critical factor in the reconstruction of the AgrC proteoliposome, in which AgrC maintained similar orientation and function as those in natural biological membranes. Two monomers, namely, rhein and aloeemodin, were successfully screened out as inhibitors targeting AgrC by the proteoliposome‐based model from 14 traditional Chinese medicine monomers. The inhibitory effects of these compounds on the growth of suspended bacteria was dose dependent, and subinhibitory concentrations of these compounds significantly reduced the expression of three virulence factors (hla, clfA and clpP), that are regulated by the agr system. The results preliminarily indicated that rhein and aloeemodin can inhibit the agr signaling pathway and also indirectly confirmed the feasibility and effectiveness of the AgrC proteoliposome as a drug screening model.

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