Microorganisms · Published 2026-08-01 · DOI 10.3390/microorganisms14081692
Xiaokun Zhan, Lifeng Zhou, Hanyu Wang, Lihao Wang, Lizhi Tian, Yonglin Zhou, Kuan Gu, Houru Liu
The increased occurrence of tetracycline resistance (conferred by the <i>tet</i>(X3)/<i>tet</i>(X4) resistance genes) poses a major challenge to the clinical treatment of infections using tetracyclines, including tigecycline, which is the “last-resort” therapeutic agent. Thus, there is an urgent need to develop inhibitors targeting Tet(X3)/Tet(X4) to address the crisis of tetracycline resistance. This study revealed that quercetin is an inhibitor of Tet(X3)/Tet(X4), which, when combined with different tetracyclines, can exert synergistic growth-inhibitory effects against Tet(X3)/Tet(X4)-positive bacteria (fractional inhibitory concentration < 0.5). Quercetin + tigecycline significantly decreased the biofilm-forming ability of bacteria. Mechanistic investigations revealed that quercetin inhibits the catalytic activity of Tet(X4) against tetracycline antibiotics by binding to the catalytic active site. In the <i>Galleria mellonella</i> larval infection model of Tet(X4)-positive <i>E. coli</i> J53p47EC or Tet(X4)-negative <i>E. coli</i> J53, tigecycline + quercetin enhanced the survival rate, decreased melanization, and suppressed bacterial load. Thus, the findings of this study will enable the development of novel Tet(X3)/Tet(X4)-targeted therapeutic strategies for clinical infections caused by drug-resistant <i>Enterobacteriaceae</i> and <i>Acinetobacter baumannii</i>, especially Tet(X3)/Tet(X4)-positive pathogens.
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Zhan, X., Zhou, L., Wang, H., et al. (2026). The Role of Natural Flavonoid Quercetin in Combating Tet(X3)/Tet(X4)-Positive Bacterial Infections. Microorganisms. https://doi.org/10.3390/microorganisms14081692