Tackling antimicrobial resistance with small-molecules targeting LsrK: challenges and opportunities

Pasquale Linciano, Valeria Cavalloro, Emanuela Martino, Johannes Kirchmair, Roberta Listro, Daniela Rossi, Simona Collina

J. Med. Chem., 2020

Antimicrobial resistance (AMR) is a growing threat to severe health and economic consequences. The available antibiotics are losing efficacy, and the hunt for alternative strategies is a priority. Quorum Sensing (QS) controls biofilm and virulence factors production. Thus, the quenching of QS to prevent pathogenicity and increase bacterial susceptibility to antibiotics is an appealing therapeutic strategy. The phosphorylation of Autoinducer-2 (a mediator in QS) by LsrK is a crucial step in triggering the QS cascade. Thus, LsrK represents a valuable target in fighting AMR. Few LsrK inhibitors have been
reported so far, allowing ample room for further exploration. This perspective aims to provide a comprehensive analysis of the current knowledge about the structural and biological properties of LsrK and the state-of-the-art technology for LsrK inhibitor design. We elaborate on the challenges in developing novel LsrK inhibitors and point out promising avenues for further research.

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