Development of new types of antimicrobial agents
The increasing resistance of bacteria to antibiotics poses an urgent health problem worldwide. As all current antimicrobials act by interfering with bacterial growth, they tend to select for resistant bacterial variants. A focus of our research is to develop novel classes of antimicrobials that act selectively on bacterial virulence without affecting growth. Potential advantages of such agents are that they are unlikely to select for resistant forms, and that they will not interfere with the commensal bacteria which normally live in the gut. In this regard, we have discovered the first antibacterial that inhibits a key virulence regulator by blocking its ability to bind to DNA. As predicted, this agent does not select for resistant variants or disrupt the gut microbiota.
Figure 1: Computer-derived docking model showing the interaction of Regacin with the DNA-binding domain of the RegA protein, which is the master regulator of Citrobacter rodentium, an E. coli-like pathogen of mice. (Ref. J. Yang et al. J Biol Chem 2013; 288: 31115-26). Proteins similar to RegA occur in many important human pathogens, including EPEC, Shigella and Vibrio cholerae.
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