Pseudomonas aeruginosa is a Gram-negative bacterium, typically affecting the lungs, urinary tract and wounds, leading to severe infections. Treatment is becoming increasingly challenging due to the rapid emergence of drug-resistant strains. Recently, significant efforts have been put into the development of the ‘pathoblockers’ – agents capable of blocking bacterial virulence by disarming the pathogen, rather than killing it. Among a vast number of virulence factors secreted by P. aeruginosa, elastase (LasB) plays a crucial role in the infection process and is considered as a promising target for the development of new inhibitors.1,2 Here, we report on the structure-based optimization of our N-arylmercaptoacetamides, resulting in two highly potent chemical classes. We pursued rigidification and a structure-based fragment growing. Freezing the active conformation in the form of succinimides enhanced the activity toward LasB two-fold compared to our previously published inhibitors and improved chemical stability with regard to disulfide formation.3,4 On the other hand, exploiting structure-based design, fragment growing of the original hit led to a substantial 16-fold boost in activity.5 In addition to the substantial increase in the potency, our new derivatives show no cytotoxicity and are highly selective for the bacterial metalloproteases over human matrix metalloproteases. Having demonstrated an excellent in vivo effect in a Galleria mellonella infection model, one of the selected inhibitors was further evaluated for its pharmacokinetic profile in mice and was subjected to an advanced SafetyScreen44 panel. Taken together, our inhibitors hold a lot of potential as novel therapeutics in the form of an adjunctive therapy for P. aeruginosa-derived infections.

Discovery of submicromolar inhibitors of the virulence factor LasB from pseudomonas aeruginosa using rational design

ACS Fall 2021

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