Optimisation of bi-therapy inhibition of Staphylococcus aureus in persistent and bacteremic infections
( StopStaphGrowth )
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.
- Alexandra Gruss, INRAE, French National Institute for Agriculture, Food and Environment, France (Coordinator)
- Patrick Trieu-Cuot, Institut Pasteur, France (Partner)
- Lorena Tuchscherr, Jena University Hospital, Germany (Partner)
- Asmaa Tazi, Institut Cochin, France (Partner)
- Pablo Taboada, University of Santiago de Compostela, Spain (Partner)
Staphylococcus aureus is a common commensal bacterium with reservoirs in healthy individuals. However, infections due to S. aureus are notoriously difficult to treat in health-compromised individuals, especially if bacteria are antibiotic-resistant, and/or if antibiotics fail to reach the infected area. Much current research aims at finding new antibiotics, repurposing old drugs, and developing combination therapies. However, drugs that work in the lab may not work in real infection situations, and efforts need to address drug functionality in the host, and its access to infected areas. The current project combines these two objectives. It relies first on the development of a bi-therapy approach in which one antibiotic reaches its target and lowers virulence factor production, and another reinforces killing of the weakened bacteria. The most potent pre-selected bi-therapy couples will be enveloped in nanoliposomes, which are potent carriers already proven effective in various clinical treatments, including vaccines (like Covid), and for antibiotic delivery. Efficacy testing of bi-therapy, freely administered or encapsulated inside nanoliposome carriers, will be done in chronic and fulminant infection conditions. This study is unique in that it provides unique bi-therapy couples and confronts the difficulties of antibiotic access in both types of potential S. aureus infections. The use of known drugs will accelerate applications of our findings.