Project

Staphylococcus aureus is a major cause of fulminant and persistent intracellular infections associated with antimicrobial resistance. Treatment failure correlates with antibiotic resistance and poor antibiotic penetration. We propose an original bi-therapy approach to treat S. aureus infections applicable to humans and animals. It is based on a large family of fatty acid synthesis (FASII) inhibitors, developed to block Firmicute pathogens. We proved that anti-FASII efficiently blocks its target but does not inhibit bacterial multiplication in the host. Instead, anti-FASII-treated bacteria use available host fatty acids, and are markedly reprogrammed, notably with diminished virulence factor expression. We identified five classes of antimicrobials that synergize with anti-FASII to block S. aureus multiplication in vitro: pore formers, stringent response inducers, wall and wall teichoic acid inhibitors, and redox cycling inhibitors. This project aims to transpose our promising in vitro findings to test feasibility of inhibiting S. aureus in intracellular and in vivo models. Selected bi-therapy couples will be encapsulated in lipidic nanoparticles to increase their penetration to solve the difficulties of access in deep and intracellular infections. This multiple-approach project is designed to provide a multimodal therapeutic approach to be used in treatments. The strategy involves compounds already used in humans or in preclinical and clinical trials, promising a rapid application of successful combinations for eradicating bacteria in hard-to-treat infections.