Staphylococcus aureus is a bacterial pathogen that causes food poisoning, various infections, and sepsis. Effective strategies and new drugs are needed to control S. aureus associated infections due to the emergence and rapid dissemination of antibiotic resistance. In the present study, the antibacterial activity, potential mode of action, and applications of flavonoids from licorice were investigated. Here, we showed that glabrol, licochalcone A, licochalcone C, and licochalcone E displayed high efficiency against methicillin-resistant Staphylococcus aureus (MRSA). Glabrol, licochalcone A, licochalcone C, and licochalcone E exhibited low cytotoxicity without hemolytic activity based on safety evaluation. Glabrol displayed rapid bactericidal activity with low levels of resistance development in vitro. Meanwhile, glabrol rapidly increased bacterial membrane permeability and dissipated the proton move force. Furthermore, we found that peptidoglycan, phosphatidylglycerol, and cardiolipin inhibited the antibacterial activity of glabrol. Molecular docking showed that glabrol binds to phosphatidylglycerol and cardiolipin through the formation of hydrogen bonds. Lastly, glabrol showed antibacterial activity against MRSA in both in vivo and in vitro models. Altogether, these results suggest that glabrol is a promising lead compound for the design of membrane-active antibacterial agents against MRSA and can be used as a disinfectant candidate as well.

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Hyperinflammation elicited by lipopolysaccharide (LPS) that derives from multidrug‐resistant Gram‐negative pathogens, leads to a sharp increase in mortality globally. However, monotherapies aiming to neutralize LPS often fail to improve the prognosis. Here, an all‐in‐one drug delivery strategy equipped with bactericidal activity, LPS neutralization, and detoxification is shown to recognize, kill pathogens, and attenuate hyperinflammation by abolishing the activation of LPS‐triggered acute inflammatory responses. First, bactericidal colistin results in rapid bacterial killing, and the released LPS is subsequently sequestered. The neutralized LPS is further cleared by acyloxyacyl hydrolase to remove secondary fatty chains and detoxify LPS in situ. Last, such a system shows high efficacy in two mouse infection models challenged with Pseudomonas aeruginosa. This approach integrates direct antibacterial activity with in situ LPS neutralizing and detoxifying properties, shedding light on the development of alternative interventions to treat sepsis‐associated infections.

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