DPD-Inspired Discovery of Novel LsrK Kinase Inhibitors: An Opportunity To Fight Antimicrobial Resistance

Antibiotic resistance is posing a
continuous threat to global public health and represents a huge burden
for society as a whole. In the past decade, the interference with
bacterial quorum sensing (QS) (i.e., cell–cell communication)
mechanisms has extensively been investigated as a valid therapeutic
approach in the pursuit of a next generation of antimicrobials. (S)-4,5-Dihydroxy-2,3-pentanedione, commonly known as (S)-DPD, a small signaling molecule that modulates QS in
both Gram-negative and Gram-positive bacteria, is phosphorylated by
LsrK, and the resulting phospho-DPD activates QS. We designed and
prepared a small library of DPD derivatives, characterized by five
different scaffolds, and evaluated their LsrK inhibition in the context
of QS interference. SAR studies highlighted the pyrazole moiety as
an essential structural element for LsrK inhibition. Particularly,
four compounds were found to be micromolar LsrK inhibitors (IC50 ranging between 100 μM and 500 μM) encouraging
further exploration of novel analogues as potential new antimicrobials.