Hit‐to‐lead optimization is a critical phase in drug discovery. Herein, we report on the fragment‐based discovery and optimization of 2‐aminopyridine derivatives as a novel lead‐like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa. We pursue an innovative treatment strategy by interfering with the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target‐driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)‐enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti‐virulence potency.

Cyclomarins are highly potent antimycobacterial and antiplasmodial cyclopeptides isolated from am arine bacterium (Streptomyces sp.). Previous studies have identified the targetp roteins and elucidated an ovel mode of action,h owever there are currently only af ew studies examining the structure-activity relationship (SAR) for both pathogens. Herein, we report the synthesisa nd biological evaluation of 17 novel desoxycyclomarin-inspired analogues. Optimization via side chain modificationso ft he non-canonical amino acids led to potentl ead structures for each pathogen. Figure 1. Structure diversity of cyclomarins.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

No abstract