The use of antibiotics has greatly improved the treatment of bacterial infections; however, its abuse and misuse has led to a rapid rise in multidrug-resistant (MDR) bacteria. Therefore, the search for new antimicrobial strategies has become critical. Natural flavonoids, a class of widely existing phytochemicals, have gained significant research interest for their diverse biological activities and antibacterial effects on various drug-resistant bacteria. This review summarizes the latest research progress on flavonoids, with a particular focus on several flavonoids exhibiting certain antibacterial activity, and explores their antibacterial mechanisms, including disruption of cell membranes and cell walls, inhibition of proteins and nucleic acids, interference with signal transduction, suppression of efflux pump activity, and inhibition of biofilm formation and virulence factor production. Additionally, we have reviewed the synergistic combinations of flavonoids with antibiotics, such as the combination of quercetin with colistin or EGCG with tetracycline, which significantly enhance therapeutic efficacy.

Bacterial drug resistance is becoming an increasingly serious problem, and the development of antibacterial synergists is urgently needed. Combining existing antibiotics with promising nonantibiotic agents is one strategy that has been shown to be effective at overcoming the widespread emergence of antibiotic-resistant pathogens. In this study, we investigated the antibacterial activities and mechanism of naringenin (NG) combined with amikacin (AMK) against multidrug-resistant Escherichia coli (E. coli). We first measured the fractional inhibitory concentration (FIC) of NG combined with antibiotics via the checkerboard method. The results indicated that the combination of NG and AMK had a synergistic effect on E. coli ATCC 25922 and E. coli C7F3. In addition, this synergistic effect was verified by time-kill assays. Moreover, scanning electron microscopy (SEM) was used to observe cell morphology. The results showed that the cell wall of E. coli was destroyed. Furthermore, we assessed the leakage of alkaline phosphatase (AKP), K⁺, and protein. The extracellular AKP activity increased after the combinational group of 1/2MIC NG and 1/2MIC AMK, suggesting an impairment in cell wall permeability. An increase in the leakage of intracellular K⁺ and protein indicated an increase in cell inner membrane permeability. These results revealed that NG and AMK inhibited E. coli by damaging cell walls and membranes. In addition, PI uptake rapidly increased after treatment with NG and AMK. Confocal laser scanning microscopy (CLSM) revealed that NG caused cell wall and cell membrane damage in E. coli. In summary, our results provide a new strategy for responding to the development of E. coli drug resistance.

Rutin is a widely known plant secondary metabolite that exhibits multiple physiological functions. The present study focused on screening for synergistic antibacterial combinations containing rutin, and further explored the mechanisms behind this synergy. In vitro antibacterial test results of rutin showed that the ranges of minimum inhibitory concentration (MIC) and Minimum bactericidal concentration (MBC) are 0.125–1 and 0.125–2 mg/mL, respectively. However, rutin and amikacin have a significant synergistic effect, with a fractional inhibitory concentration index (FICI) range of 0.1875–0.5. The time bactericidal curve proved that the combination of rutin and amikacin inhibited bacterial growth within 8 h. Scanning electron microscopy (SEM) revealed that a low-dose combination treatment could disrupt the cell membrane of Escherichia coli (E. coli). A comprehensive analysis using alkaline phosphatase (AKP), K⁺, and a protein leakage assay revealed that co-treatment destroyed the cell membrane of E. coli, resulting in the significant leakage of AKP, intracellular K⁺, and proteins. Moreover, confocal laser scanning microscopy (CLSM) and red–green cell ratio analysis indicated severe damage to the E. coli cell membrane following the co-treatment of rutin and amikacin. This study indicates the remarkable potential of strategically selecting antibacterial agents with maximum synergistic effect, which could significantly control antibiotic resistance.

Background: The rapid emergence of antibiotic resistance in E. coli has outpaced the development of new drugs, creating an urgent demand for novel therapeutic strategies. Methods: We screened ten antibiotics in combination with isochlorogenic acid C (ICAC) against multidrug-resistant (MDR) E. coli. Synergistic effects of antibiotics and ICAC were evaluated by measuring the leakage of alkaline phosphatase (AKP), potassium ions (K⁺), as well as changes in total protein, and ATP levels. The integrity of bacterial membrane and cell wall was visualized by SEM and CLSM. The underlying mechanisms were elucidated via proteomic analysis and molecular docking. Finally, the protective effect of ICAC in vivo was evaluated using an intraperitoneal infection model in SPF female BALB/c mice. Results: ICAC exerted a specific synergistic effect with ciprofloxacin, significantly enhancing its efficacy. The combination disrupted bacterial membrane and cell wall integrity, increased permeability, and inhibited ATP synthesis. Mechanistically, ICAC may target OmpF and inhibit fatty acid biosynthesis. This interference reduced β-oxidation and the influx of acetyl-CoA into the TCA cycle, thereby impairing bacterial energy metabolism and destabilizing the membrane. In vivo validation using a mouse peritonitis model confirmed that the combination treatment effectively alleviated systemic E. coli infection. Conclusion: ICAC may potentiate the antibacterial activity of ciprofloxacin through targeting of OmpF, which disrupts bacterial membrane integrity and energy metabolism, providing a promising candidate strategy for combating infections caused by the tested antibiotic-resistant E. coli.