Sanguinarine Inhibits the 2-Ketogluconate Pathway of Glucose Utilization in Pseudomonas aeruginosa

Abstract

Interfering with the ability of pathogenic bacteria to import glucose may represent a new promising antibacterial strategy, especially for the treatment of infections occurring in diabetic and other hyperglycemic patients. Such patients are particularly susceptible to infections caused by a variety of bacteria, among which opportunistic pathogens like Pseudomonas aeruginosa. In P. aeruginosa, glucose can be directly imported into the cytoplasm or after its periplasmic oxidation into gluconate and 2-ketogluconate (2-KG). We recently demonstrated that a P. aeruginosa mutant lacking the 2-KG transporter KguT is less virulent than its kguT+ parental strain in an insect infection model, pointing to 2-KG branch of glucose utilization as a possible target for anti-Pseudomonas drugs. In this work, we devised an experimental protocol to find specific inhibitors of the 2-KG pathway of P. aeruginosa glucose utilization and applied it to the screening of the Prestwick Chemical Library. By exploiting mutants lacking genes involved in the transport of glucose derivatives in the primary screening and in the secondary assays, we could identify sanguinarine as an inhibitor of 2-KG utilization. We also demonstrated that sanguinarine does not prevent 2-KG formation by gluconate oxidation or its transport, suggesting that either KguD or KguK is the target of sanguinarine in P. Aeruginosa.

Phytochemicals as Invaluable Sources of Potent Antimicrobial Agents to Combat Antibiotic Resistance

“…It has been shown that the P. aeruginosa mutant that lacks 2-ketogluconate transporter was relatively less pathogenic than wild-type P. aeruginosa [52]. Falchi and colleagues demonstrated that sanguinarine suppresses the 2-ketogluconate pathway of glucose utilization in P. aeruginosa by either targeting KguD or KguK [53]. In another report, sanguinarine induced an antibacterial effect against MRSA by triggering the release of membrane-bound cell wall autolytic enzymes, which eventually leads to bacterial lysis [54].…”

Preclinical safety evaluation of Macleaya Cordata extract: A re-assessment of general toxicity and genotoxicity properties in rodents

“…(Warowicka et al, 2019;Lu et al, 2020). They have a wide range of pharmacological activities, such as anti-inflammatory (Danielewski et al, 2022), anti-cancer (Zhu et al, 2020;Prabhu et al, 2021), antibacterial (Falchi et al, 2021;Lu et al, 2022), antifungal (Anjago et al, 2021), anthelmintic (Li et al, 2022), and immune enhancing (Liu et al, 2022a), etc. The biggest application of M. cordata is in livestock production, where studies have shown that MCE can provide a slight bitter taste in feed to increase animal intake (Chin, 2008;Wang et al, 2018).…”

Sanguinarine Protects Channel Catfish against Aeromonas hydrophila Infection by Inhibiting Aerolysin and Biofilm Formation

“…Br., has antibacterial, anti-inflammatory, anti-tumor, immunity enhancement and insecticidal effects [ 17 ]. Previous studies have demonstrated that sanguinarine can inhibit the pathogenesis of several bacterial pathogens by different mechanisms [ 18 , 19 , 20 ]. However, the inhibitory effect of sanguinarine on A. hydrophila virulence has not been clarified.…”