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.
Highlights
Antimicrobial resistance (AMR) and the worldwide increase of superbug infections are recognized by the World Health Organization (WHO) as global concerns for public health and healthcare systems’ sustainability.[1,2]
Five strategic objectives were set out: (i) promotion of initiatives for raising awareness about this issue, (ii) optimization of the use of antibiotics in both human and animal health, (iii) delineation of global strategies to monitor and contain the spread of resistance, (iv) application of preventive measures to reduce the incidence of infections, and (v) incentivization of investments in the research of new pharmaceutical tools and medicines.[7]
Inappropriate prescription, and extensive agricultural use of antibiotics have exposed bacteria to intense, selective evolutive pressure. This led to the development of protective mechanisms to inactivate, remove, and, in general, circumvent the toxicity of the antibiotics against bacteria.[8−11] These mechanisms of resistance exploit the reduction of drug permeability,[12] the excretion of the antibiotic through active efflux pumps,[13] the production of antibiotic-inactivating enzymes (i.e., β-lactamases),[14−16] or the formation of biofilms,[17] conferring reduced susceptibility to antibiotic activity
Summary
Antimicrobial resistance (AMR) and the worldwide increase of superbug infections are recognized by the World Health Organization (WHO) as global concerns for public health and healthcare systems’ sustainability.[1,2] AMR infections cause approximately 700 000 deaths annually, and they are expected to become the leading cause of death by the year 2050, especially in low- and middle-income countries.[3−5] it is projected that in the year 2050, AMR could lower the global gross domestic product by up to one trillion dollars annually.[6]. AI-2 is actively released in the extracellular space by the proposed YdgG protein, other unknown mechanisms could be present (Figure 1).[81] Once a threshold concentration of AI-2 in the extracellular environment is reached, R-THMF is internalized via the Lsr (LuxS regulated) transporter system, an ATP-binding cassette.[77,82] In the cytoplasm, R-THMF, in equilibrium with the hydrated linear DPD (i.e., S-THP, Figures 1−2), is further phosphorylated at position 5 by LsrK. Additional STD-NMR studies performed by Ha et al.[89] revealed that the LsrK-HPr complex’s affinity was higher for ATP than for DPD, supporting the above consideration These experimental observations agree with superimposition studies of the LsrKHPr complex with the FGGY superfamily member in diverse conformational states (i.e., ecXK or ecGK), confirming the openinactive conformation for the newly resolved LsrK-HPr complexes.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
