Abstract Aims This study was conducted to evaluate 35 natural flavonoids for their in vitro susceptibility against E. coli (ATCC 25922), Ps. aeruginosa (ATCC 27853), B. subtilis (ATCC 530) and Staph. aureus (ATCC 6538) in search of a potential broad‐spectrum antibiotic. Methods and Results Glabridin, a natural isoflavonoid isolated from Glycyrrhiza glabra L., was identified to be highly active with a MIC of 8–16 μg ml−1 against Staph. aureus, B. subtilis and E. coli. By the results of the docking simulation, we located the potential targets of glabridin as DNA gyrase and dihydrofolate reductase (DHFR). The subsequent DNA gyrase inhibition assays (glabridin: IC50 = 0.8516 μmol L−1, ciprofloxacin: IC50 = 0.04697 μmol L−1), DHFR inhibition assays (glabridin: inhibition ratio = 29%, methotrexate: inhibition ratio = 45% under 100 μmol L−1 treatment) and TUNEL confirmed that glabridin acted as DNA gyrase inhibitor and DHFR mild inhibitor, exerting bactericidal activity by blocking bacterial nucleic acid synthesis. CCK‐8 and in silico calculations were also conducted to verify the low cytotoxicity and acceptable druggability of glabridin. Conclusion These findings suggest that glabridin represents the prototypical member of an exciting structural class of natural antimicrobial agents. Significance and Impact of the Study This study reports a novel mechanism of bactericidal activity of glabridin against Staph. aureus.
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