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.

As an opportunistic pathogen, Escherichia coli (E. coli) forms biofilm that increases the virulence of bacteria and antibiotic resistance, posing a serious threat to human and animal health. Recently, ginkgetin (Gin) has been discovered to have antiinflammatory, antioxidant, and antitumor properties. In the present study, we evaluated the antibiofilm and antibacterial synergist of Gin against E. coli. Additionally, Alamar Blue assay combined with confocal laser scanning microscope (CLSM) and crystal violet (CV) staining was used to evaluate the effect of antibiofilm and antibacterial synergist against E. coli. Results showed that Gin reduces biofilm formation, exopolysaccharide (EPS) production, and motility against E. coli without limiting its growth and metabolic activity. Furthermore, we identified the inhibitory effect of Gin on AI-2 signaling molecule production, which showed apparent anti-quorum sensing (QS) properties. The qRT-PCR also indicated that Gin reduced the transcription of curli-related genes (csgA, csgD), flagella-formation genes (flhC, flhD, fliC, fliM), and QS-related genes (luxS, lsrB, lsrK, lsrR). Moreover, Gin showed obvious antibacterial synergism to overcome antibiotic resistance in E. coli with marketed antibiotics, including gentamicin, colistin B, and colistin E. These results suggested the potent antibiofilm and novel antibacterial synergist effect of Gin for treating E. coli infections.

The spread of multidrug-resistant bacteria around the world is rising, and new antibiotics are urgently needed to address the drug resistance crisis. Natural products have become a focal point in the research and development of antibacterial drugs, owing to their structural diversity and biological activity. Kaempferol, in particular, exhibits a range of biological properties, including antioxidant, antibacterial, and antitumor activities, and holds potential for application across various domains. This review aims to provide a comprehensive overview of the extraction, biosynthesis, and antibacterial activity of kaempferol, as well as to elucidate its antibacterial mechanisms. In addition, we also reviewed the synergistic combination of kaempferol with antibiotics, such as the combination of kaempferol with colistin or penicillin, which significantly improved their therapeutic effect. Finally, the preparation of kaempferol nanoparticles and their applications in antibacterial treatments were discussed.

Biofilm formation constitutes a major factor in antibiotic treatment failure, shielding bacteria from drugs and promoting persistence. This study demonstrates that the anti-biofilm action of clove oil enhances the efficacy of fosfomycin against Escherichia coli O157:H7 (E. coli O157). Using a luxS-eGFP reporter system, it was found that clove oil inhibited E. coli O157 biofilm formation by up to 80% via suppression of the LuxS/AI-2 quorum sensing (QS) system and bacterial motility. Crucially, this disruption was shown to correlate with a strong synergistic effect when combined with fosfomycin in vitro. In a murine peritoneal infection model, the combination therapy demonstrated superior efficacy compared to monotherapy. Specifically, bacterial loads in the liver, spleen, and small intestine were significantly reduced, and histopathological damage was alleviated. Mechanistically, these effects were linked to the downregulation of the QS. These findings indicate that clove oil acts as a potent adjuvant to fosfomycin by disrupting biofilms, offering a promising strategy against systemic infections caused by E. coli O157.

Toxoplasmosis is a significant zoonotic parasitic disease. Currently, there is no effective vaccine available to prevent human infection, and treatment primarily relies on chemotherapy. However, the lack of specific therapeutic agents and the limitations of existing drugs highlight the urgent need for novel, safe, and effective anti-Toxoplasma gondii (T. gondii) medications. In this study, we evaluated the toxicity of ICA (N-(pyridin-2-yl)-4-(pyridine-2-yl)thiazol-2-amine) to host cells and assessed its inhibitory and anti-proliferative effects on T. gondii tachyzoites. We further investigated the impact of ICA on the ultrastructure of T. gondii using transmission electron microscopy (TEM). Additionally, we measured alterations in mitochondrial membrane potential, superoxide levels, and ATP levels in T. gondii to assess the effect of ICA on mitochondrial function. Our findings demonstrated that ICA exhibits a safe and effective inhibitory effect on T. gondii, with a selectivity index (SI) of 258.25. Notably, ICA demonstrated a more potent anti-proliferative effect than pyrimethamine (PYR). Ultrastructural observations revealed that ICA induces mitochondrial swelling and membrane rupture in T. gondii. Further investigations confirmed that ICA leads to mitochondrial dysfunction in T. gondii. In conclusion, our results suggest that ICA possesses the potential to serve as a lead compound for the development of novel anti-T. gondii therapies.

Toxoplasmosis is a zoonotic disease with limited therapeutic options, which are further hampered by significant toxicity and suboptimal efficacy. Effective interventions for chronic infection remain insufficient, and thus, natural product-derived drug screening remains a key focus in anti-Toxoplasma research. Licochalcone A (Lico A), a major bioactive compound isolated from Glycyrrhiza uralensis, exhibits potent activity against Toxoplasma tachyzoites. However, systematic studies of its targets, pharmacokinetics, and efficacy are lacking, hindering its development as an anti-Toxoplasma candidate drug. In this study, we used SPR-MS to identify 33 high-affinity target proteins (affinity score > 1000). Furthermore, an AI-driven multidimensional analysis identified a cluster of five proteins (TgMORN1, D3XD37, ABCB2, MIC15, and IDH), with TgMORN1 yielding the highest composite score. RNAi experiments confirmed TgMORN1 as a key target, as its silencing attenuated the anti-proliferative effect of Lico A. Western blotting, NanoDSF, and SPR supported direct binding between Lico A and TgMORN1, suggesting that Lico A modulates TgMORN1 thermal stability through residues S168 and D203, with high species specificity. Pharmacokinetic evaluation revealed that Lico A had favorable absorption and blood–brain barrier permeability, supporting its potential utility in treating brain disease. In vitro assays showed that Lico A effectively inhibited Toxoplasma gondii brain cyst formation. Collectively, these findings support Lico A as a promising candidate for the treatment of toxoplasmosis.