Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy.
Department of Earth and Environmental Science, University of Pavia, Via Sant'Epifanio 14, 27100 Pavia, Italy.
J Med Chem. 2020 Dec 24;63(24):15243-15257. doi: 10.1021/acs.jmedchem.0c01282. Epub 2020 Nov 5.
Antimicrobial resistance (AMR) is a growing threat with 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 to 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.
抗菌药物耐药性（AMR）是一个日益严重的威胁，对健康和经济造成严重后果。现有的抗生素正在失去疗效，因此寻找替代策略是当务之急。群体感应（QS）控制生物膜和毒力因子的产生。因此，抑制 QS 以防止致病性并增加细菌对抗生素的敏感性是一种有吸引力的治疗策略。LsrK 对自诱导物-2（QS 中的一种介质）的磷酸化是触发 QS 级联的关键步骤。因此，LsrK 是对抗 AMR 的一个有价值的靶点。迄今为止，已经报道了少数 LsrK 抑制剂，为进一步探索提供了充足的空间。本观点旨在对 LsrK 的结构和生物学特性以及 LsrK 抑制剂设计的最新技术进行全面分析。我们详细阐述了开发新型 LsrK 抑制剂所面临的挑战，并指出了进一步研究的有前途的途径。
