D3*
Anti-virulence agents to prevent and treat Salmonella infections
Prof. Samuel Wagner, Universitätsklinikum Tübingen; Dr Abdelhakim Boudrioua, Universutätsklinikum Tübingen; Dr Iwan Grin, Universitätsklinikum Tübingen; Dr Joe Joiner, Max-Planck-Institut für Biologie; Prof. Mark Brönstrup, Helmholtz-Zentrum für Infektionsforschung; Dr Vadim Korotkov, Helmhotz-Zentrum für Infektionsforschung; Dr Arun Naini, Helmholtz-Zentrum für Infektionsforschung; Dr Simon Kalverkamp, Helmholtz-Zentrum für Infektionsforschung; Dr Thales Kronenberger, Universitätsklinikum Tübingen; Dr Marcus Hartmann, Max-Planck-Institut für Biologie; Prof. Antti Poso, Universitätsklinikum Tübingen
Universitätsklinikum Tübingen
Challenge
Prevention and treatment of enteric infections caused by non-Typhoidal Salmonella. The incidence of this infection is 150 million cases resulting in 300 000 deaths annually. Fluoroquinolone antibiotic class as established standard-of-care suffered from widespread resistance development and black-box safety warnings. Antibiotics generally not indicated for preventing infection/disease.
Technology
A synthetic small molecule that inhibits a key positive regulator of Salmonella pathogenicity. The compound blocks Salmonella invasion into human host cells.
The compound can be developed as a standalone or combination therapy with standard-of-care antibiotic.
Commercial Opportunity
- Preventive drug for the prevention of traveler’s diarrhea caused by Salmonella. Target HICs.
- Standalone treatment to reduce the risk of invasive infection in patients developing an enteric Salmonella infection. Target HICs, UMICs, LMICs.
- Standalone treatment to shorten hospitalization of patients developing an enteric Salmonella infection. Target HICs, UMICs, LMICs.
- Combination with standard-of-care antibiotic for the treatment of invasive and antibiotic resistant Salmonella infections. Target all income groups.
Development Status
- At hit-to-lead optimization stage.
- Protein target identified as HilD, the central regulator of invasive Salmonella pathogenicity. Activity at low µM scale.
- Mode of action deciphered: The inhibitor leads to a downregulation of HilD-regulated genes, resulting in blocking the expression and assembly of secretion systems that are necessary for invasion.
- Target-ligand complex characterized: The binding pocket is localized at the junction between the regulatory domain and the signal receiver/dimerization domain. The inhibitor binds to HilD and subsequently inhibits its ability to bind to the promoter region of regulated virulence genes.
- Advanced structure-activity-relationship: 160 structural analogs synthesized and tested with an in-house developed call-based assay to quantify HilD inhibition. SAR established. More than 15 analogs showed improved activity.
- Resistance development assessed.
- In vitro ADMETox performed and showed satisfying profile.
- In vivo toxicity in mice showed no toxicity of the inhibitor at 30 mg/kg.
- In vivo potency in a mouse model of Salmonella infection expected during Q1 of 2023.
Patent Situation
The application is being handled by the technology transfer office of Universitätsklinikum Tübingen. It is planned to be submitted during Q1 of 2023.
Further Reading
- Galán, Jorge E. “Salmonella Typhimurium and Inflammation: A Pathogen-Centric Affair.” Nature Reviews Microbiology, May 2021, pp. 1–10, doi.org/10.1038/s41579-021-00561-4.
- Dickey, Seth W., et al. “Different Drugs for Bad Bugs: Antivirulence Strategies in the Age of Antibiotic Resistance.” Nature Reviews Drug Discovery, vol. 16, no. 7, July 2017, pp. 457–71, doi.org/10.1038/nrd.2017.23.
- European Centre for Disease Prevention and Control. Salmonellosis. In: ECDC. Annual Epidemiological Report for 2020. Stockholm: ECDC; 2022.
