The Role of Natural Flavonoid Quercetin in Combating Tet(X3)/Tet(X4)-Positive Bacterial Infections
Abstract
The increased occurrence of tetracycline resistance (conferred by the tet(X3)/tet(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 Galleria mellonella larval infection model of Tet(X4)-positive E. coli J53p47EC or Tet(X4)-negative E. coli 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 Enterobacteriaceae and Acinetobacter baumannii, especially Tet(X3)/Tet(X4)-positive pathogens.
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