In the fight against antibiotic resistance the search for novel drug targets is of high priority. Bacterial type I signal peptidase of Escherichia coli, known as LepB, is a potential target for the development of novel antibiotics. Recently, a set of cationic lipopeptides have been discovered that potently inhibited the LepB enzyme and showed good antimicrobial activity. However, the cytotoxicity and hemolytic profiles of these compounds were not optimal, suggesting that further optimization is needed to develop a promising lead compound. Therefore, we have developed novel macrocyclic lipopeptides, linking P2 and P1’ by a boronic ester warhead, capable of inhibiting Escherichia coli type I signal peptidase (EcLepB) and exhibiting good antibacterial activity. Structural modifications of the macrocyclic ring, the peptide sequence and the lipophilic tail led us to 14 novel macrocyclic boronic esters. Among the synthesized macrocycles, potent enzyme inhibitors in the low nanomolar range (e.g. compound 42f, EcLepB IC50 = 29 nM) were identified also showing good antimicrobial activity (e.g. compound 42b, E. coli WT MIC = 16 µg/mL). The unique macrocyclic boronic esters described here were based on previously published linear lipopeptidic EcLepB inhibitors in an attempt to address cytotoxicity and hemolysis. We show herein that structural changes to the macrocyclic ring influence both the cytotoxicity and hemolytic activity suggesting that the P2 to P1’ linker provide means for optimizing off-target effects. However, for the present set of compounds we were not able to separate the antibacterial activity and cytotoxic effect.

Novel macrocyclic lipopeptides as serine protease inhibitors targeting Escherichia coli type I signal peptidase

2019 Fall National Meeting

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