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

Journal of Medicinal Chemistry
Silvia StotaniSimona Collina

Abstract

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.

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Citations

Feb 7, 2020·Chembiochem : a European Journal of Chemical Biology·Viviana GattaPäivi Tammela
Mar 20, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Zeinab BreijyehRafik Karaman
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Mar 9, 2021·Journal of Chemical Information and Modeling·Prasanthi MedarametlaAntti Poso
Jan 21, 2022·Future Medicinal Chemistry·Mohammad A Alam

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