Pseudomonas aeruginosa (PA) antibiotic resistance has led to an ongoing crisis in treatment options in human healthcare with a prevalence of multi-drug resistant PA of 15–30% in some areas. Besides being a common cause of nosocomial infections, PA also plays a major role in chronic stadiums of cystic fibrosis (CF). Consequently, there is urgent need for new treatment options addressing new targets to overcome resistance problems. A relatively new approach is to target the production of PA’s virulence factors, of which pyocyanin is one of the most studied. This phenazine plays a crucial role in redox activity, forming of reactive oxygen species and uptake of iron, making it one of the major virulence factors involved in chronic stadiums of CF. The approved drug raloxifene is known to inhibit pyocyanin production in cellulo, likely targeting the biosynthesis enzyme PhzB of PA. In this work, we developed raloxifene-based PhzB inhibitors by performing molecular docking studies and synthesizing raloxifene analogs modified in the 4’-position of the 3-benzoyl moiety. The synthesized inhibitors were subsequently co-crystallized with BcPhz(A)/B from Burkholderia cepacia. After introduction of an additional hydroxyl group, a novel binding mode was observed that differed from both the docking results as well as the raloxifene-like binding mode of most other analogs. Since in vitro activity was maintained, this offers the possibility to design raloxifene-based PhzB inhibitors with presumably reduced estrogenic activity.

Raloxifene-based PhzB inhibitor exhibits novel binding mode

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