Design, Synthesis, and Evaluation of Novel Elastase (LasB) Inhibitors: A Promising Strategy to Combat Pseudomonas aeruginosa Virulence and Antibiotic Resistance

Antibiotic resistance is an important global health issue, and Pseudomonas aeruginosa is a pathogen that is particularly worrying due to its ability to become virulent and multidrug-resistant. One of the main mechanisms by which P. aeruginosa exerts its virulence is through the production of elastase (LasB), an extracellular metalloprotease involved in the disturbance of the host immune system.

Several compounds have succeeded in suppressing LasB activity, but their lack of stability and selectivity has prevented further development. We have successfully designed and synthesized a series of compounds based on co-crystal structures, enhancing inhibitory activity. The results demonstrate their efficacy as very potent LasB inhibitors, with sub-nanomolar inhibition constants (IC50 = 0.49–7.7nM). Furthermore, these compounds have demonstrated good stability and selectivity over human off-targets. In addition to these achievements, we have strategically addressed plasma protein binding (PPB), lowering it to align with the lung exposure range. 

In addition to in vitro tests, promising results were obtained in in vivo PK studies, which paved the way to demonstrate in vivo efficacy and target engagement in a murine lung infection model. Our research provides evidence of the success of the design of a new LasB inhibitor class that can be optimized and further developed as a potential therapeutic to reduce P. aeruginosa virulence. Additional biological and pharmacological tests will be presented, which highlight the potential of these compounds as a new class of LasB inhibitors for the treatment of infections caused by P. aeruginosa.