OE-OH to Address AMR: Antibacterial Quantitative Structure–Activity Relationship Models and Syner-gistic Effects with Clinical Antibiotics for Natural Quinones

Background/Objectives: Antimicrobial resistance (AMR) poses a great threat to human health, and combination therapy is effective for its control. Previous work has performed for the antimicrobial quantitative structure–activity relationship (QSAR) models and synergistic antibacterial effects with clinical antibiotics of plant flavonoids. This study investigated whether antimicrobial QSAR models can be constructed for natural quinones and whether these compounds also exert extensive synergism when combined with clinical antibiotics. Methods: The antibacterial activities of 18 designed quinones and 11 clinical antibiotics with various antimicrobial mechanisms were determined using microbroth dilution method. Subsequently, the correlation and regression analyses between the minimum inhibitory concentration (MIC) and physicochemical parameter of quinones were performed for the establishment of antimicrobial QSAR models. Simultaneously, induction and deduction were applied to summarize the SARs based on the antimicrobial activity changes induced by structural variations. Finally, the combined effects of 11 quinones with 11 antibiotics against Staphylococcus aureus, together with those of 10 quinones with these antibiotics against Escherichia coli, were determined using checkerboard test. Results: Quinones exhibit potent, broad‑spectrum antimicrobial activity, particularly 5,8-dihydroxyl-1,4‑naphthoquinones with the MICs against S. aureus, E. coli, and Candida albicans of 8, 4, and 0.25 μg/mL, respectively. There are significant correlations between lipophilicity parameters and the MICs of quinones against E. coli or C. albicans, especially the former, but not for S. aureus. Interestingly, significant correlations exist between reduction potentials and the MICs of quinones against S. aureus and C. albicans, also especially the former. Subsequently, four optimal QSAR models were established for quinones against these three strains, respectively. simultaneously, several antimicrobial SARs were summarized, indicating the 5-hydroxy or 5,8-dihydroxynaphthoquinone scaffold is crucial for the inhibitory activities of naphthoquinones to C. albicans and E. coli. These QSAR and SARs further suggest that the primary target of quinones against E. coli resides in the cytoplasm or nuclear region, and while those against S. aureus is on the electron transfer process from type II NADH:quinone oxidoreductase to quinone pool in the respiratory chain. Another, quinones present moderate synergistic effects with antibiotics, while their synergistic probabilities against E. coli would remarkably increase when combined with antibiotics targeting the cell membrane. Furthermore, emodin presents extensive synergy with antibiotics whether against S. aureus or E. coli. Conclusions: Natural quinones is encouraged to be developed as novel antimicrobial agents or adjuvants. Furthermore, effective utilization of quinone‑containing biological resources especially plant to reduce the enrichment and dissemination of ARGs in ecosystems is helpful for addressing AMR according to the OE-OH.