Development of novel compounds targeting Pseudonomas aeriginosa elastase LasB
Pseudomonas aeruginosa (PA), a highly problematic Gram-negative pathogen, which has been assigned critical priority by the WHO, is responsible for many nosocomial infections. The opportunistic pathogen is also commonly found in burns, and in lungs of COPD and cystic fibrosis patients. PA-derived virulence factors play pivotal roles in mechanisms mediating its pathogenesis and infectivity. The strategy to develop “pathoblockers” targeting such virulence factors is expected to leave the commensal microbiome intact and to be less prone to the development of resistance compared to conventional antibiotics. One of the major virulence factors of PA is the extracellular zinc-metalloprotease elastase LasB. LasB substantially contributes to disease progression in PA-infected individuals by facilitating host invasion and immune evasion, and was furthermore reported to be involved in the formation of PA biofilms. Inhibition of LasB is a promising strategy to effectively reduce virulence of PA without affecting viability of the pathogen and the host microbiome. Our most promising LasB inhibitors show nanomolar IC50 values and a promising safety profile.
- Drug Design and Optimization- Prof. Dr. Anna K. H. Hirsch
HZI - Helmholtz Centre for Infection Research