Tackling Antimicrobial Resistance with Small Molecules Targeting LsrK: Challenges and Opportunities

Abstract

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.

The Case against Antibiotics and for Anti-Virulence Therapeutics

“…Quorum sensing (QS) is the process used by bacteria to control gene expression in response to cell density and external factors sensing [16][17][18]. Small molecules, called autoinducers, are produced by bacteria and release to be sensed by other bacteria.…”

“…Small molecules, called autoinducers, are produced by bacteria and release to be sensed by other bacteria. These allow a bacterial population to sense neighboring cells sensing [16][17][18]. QS is used to control a variety of critical functions related to growth, colonization, and pathogenesis.…”

“…These including biofilm formation, virulence factor deployment, and antibiotic resistance gene expression [243]. Inhibition of QS could prevent pathogenic bacteria from coordinating virulence factor usage sensing [16][17][18]. This could reduce the pathogen's infectivity, allowing the host immune system to clear the infection more effectively.…”

“…This could reduce the pathogen's infectivity, allowing the host immune system to clear the infection more effectively. QS inhibition could also increase the efficacy of existing antibiotics by virtue of inhibiting antibiotic resistance gene expression sensing [16][17][18]. This could allow existing antibiotics to have increased time as first-line therapies.…”

“…Cyclic dipeptides [250,251] Indicated in reporter assays E. coli [247], P. aeruginosa [245], and Vibrio spp. [249] In Vitro DPD derivatives [17] LrsK inhibition Salmonella spp. [252] In Vitro Epigallocatechin-3gallate [253,254] Decrease QS gene expression EHEC [247], Pseudomonas [245], Salmonella [252], and Staphylococcus spp.…”