The use of antimicrobials to control Salmonella infection in livestock and poultry has created an arms race that pits antimicrobial development against resistance acquisition by the pathogen. This is a race that we are destined to lose, and thus perpetuates the spread of antimicrobial resistance. An alternative approach is therefore needed. We propose here to identify means to inhibit the expression of Salmonella invasion genes, required for virulence and animal carriage, but without killing the pathogen, thus removing the selective pressure for acquisition of drug resistance. We hypothesize that Salmonella carriage in production animals can be controlled using chemical compounds that repress essential virulence functions of this pathogen without affecting its viability, and that such compounds can be identified by screening small molecule libraries with subsequent testing in a relevant agricultural animal species. Thus, we propose to: 1) Determine the mechanism by which chemical inhibitors affect Salmonella invasion; 2) Identify drug-like inhibitors of Salmonella invasion using a high throughput chemical library screen; 3) Determine the oral efficacy of selected compounds in reducing Salmonella carriage and shedding in chickens, and; 4) Assess the frequency and consequences of resistance to invasion inhibitors.

This work has the potential to identify new classes of chemical interventions that inhibit salmonellosis in a novel way, by affecting virulence functions. The great advantage of this approach is that, due to the mechanism of Salmonella pathogenesis, it is unlikely to generate resistant mutants. It thus presents a promising alternative to the use of antimicrobials in livestock and poultry production.