Abstract
PhoQ/PhoP is an important two-component system that regulates Shigella virulence. We explored whether the PhoQ/PhoP system is a promising target for new antibiotics against S. flexneri infection. By using a high-throughput screen and enzymatic activity coupled assay, four compounds were found as potential PhoQ inhibitors. These compounds not only inhibited the activity of SF-PhoQc autophosphorylation but also displayed high binding affinities to the SF-PhoQc protein in the Surface Plasmon Resonance response. A S. flexneri cell invasion assay showed that three of these potential PhoQ inhibitors inhibit the invasion of HeLa cells by S. flexneri 9380. In a Mouse Sereny test, mice inoculated with S. flexneri 9380 pre-treated with the potential PhoQ inhibitors 1, 2, 3 or 4 displayed no inflammation, whereas mice inoculated with S. flexneri 9380 alone displayed severe keratoconjunctival inflammation. All four potential PhoQ inhibitors showed no significant cytotoxicity or hemolytic activity. These data suggest that the four potential PhoQ inhibitors inhibited the virulence of S. flexneri and that PhoQ/PhoP is a promising target for the development of drugs against S. flexneri infection.
Highlights
Shigella is a gram-negative facultative intracellular pathogen with enhanced cell invasion, intracellular growth and intercellular spreading capabilities
An optimized 3D model of the PhoQ histidine kinase (PhoQ HK) domain of Sf301 was constructed based on the crystal structure of PhoQ HK from E .coli, which is highly homologous to S. flexneri
Bacterial two-component systems have gained increasing interest as novel antibacterial targets because these systems are required for virulence of pathogenic microorganisms [17,18]
Summary
Shigella is a gram-negative facultative intracellular pathogen with enhanced cell invasion, intracellular growth and intercellular spreading capabilities. The bacteria are transmitted fecal-orally and will invade the mucosa of the colon. Infection by only 10 to 100 organisms will cause shigellosis. Because of the overuse of antibiotics, Shigella drug resistance in clinical settings is increasing [1,2,3]. New therapeutic targets and drugs are needed to reduce the incidence of shigellosis worldwide. Understanding the regulation of Shigella virulence may lead to the development of new drugs that can inhibit or reduce the virulence of Shigella as well as provide new strategies for treating shigellosis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
