Proteoliposome‐based model for screening inhibitors targeting histidine kinase AgrC

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.

Natural Products That Target Virulence Factors in Antibiotic-Resistant Staphylococcus aureus

“…On the basis of a proteoliposome-based model, rhein and aloeemodin were found to inhibit AgrC histidine kinase activity and biofilm formation in S. aureus . Additionally, ω-hydroxyemodin of Penicillium restrictum inhibits quorum sensing via direct binding to AgrA and then suppresses interaction between AgrA and the Agr P2 promoter.…”

“…Hamamelitannin, isolated from American witch hazel, inhibits the quorum-sensing regulator RNAIII and improves the effect of antimicrobials against S. aureus. , Interestingly, xanthones (ω-hydroxyemodin, rhein, aloeemodin, and polyhydroxyanthraquinones), and cyclic peptides (AIP of S. caprae, solonamides A and B, − WS9326 A and B, and cochinmicin II and III) exhibit good inhibitory effects on the Agr quorum-sensing system and provide the basic structure skeleton for the discovery and design of better antivirulence compounds (Table ).…”

Plant Derived Natural Products against Pseudomonas aeruginosa and Staphylococcus aureus: Antibiofilm Activity and Molecular Mechanisms

“…Arylbenzylfuran was active against clinical strains of methicillin-resistant S. aureus (MRSA), and was able to induce a significant reduction in S. aureus ATCC 12600S biofilm viability [116]. Several aromatic polyketides isolated from plants have been reported, in particular aloe-emodin [117], acting against the Agr quorum-sensing system. The same compound and the structurally related rhein [117] were able to inhibit biofilm formation.…”

“…Several aromatic polyketides isolated from plants have been reported, in particular aloe-emodin [117], acting against the Agr quorum-sensing system. The same compound and the structurally related rhein [117] were able to inhibit biofilm formation.…”

Recent Advances in Histidine Kinase-Targeted Antimicrobial Agents

“…Many nonessential TCSs are evolved to control a number of virulence factors, such as biofilms and quorum sensing (QS), in response to extracellular signals and stress ( Worthington et al, 2013 ). For example, TCSs, such as AgrC/AgrA from S. aureus , PhoQ/PhoP from E. coli , and QseC/QseB from some gram-negative pathogens, including enterohemorrhagic E. coli , uropathogenic E. coli , and Salmonella enterica ( Breland et al, 2017 ), have been shown to act as regulators of bacterial virulence and pathogenesis by modulating the processes of QS, biofilm/cell envelope formation, and/or virulence ( Senadheera et al, 2005 ; George and Muir, 2007 ; Weigel and Demuth, 2016 ; Breland et al, 2017 ; Zhang et al, 2019 ; Yadavalli et al, 2020 ). Another TCS DosS-DosT/DosR from M. tuberculosis is involved in sensing host stimuli and triggering/maintaining dormancy ( Roberts et al, 2004 ; Ioanoviciu et al, 2009 ).…”