Quercetin as tigecycline adjuvant reverses multidrug-resistant Acinetobacter baumannii infection

The rise and global dissemination of multidrug-resistant (MDR) Acinetobacter baumannii has become a major public health threat. However, the constant emergence of drug-resistant mutants has resulted in increasingly limited therapeutic options. Tigecycline (TGC) continues to be one of the few antibiotics still effective against many A. baumannii strains. Herein, we discovered that quercetin (Qu) synergizes with TGC, enhancing its therapeutic efficacy against MDR A. baumannii by reducing the minimum inhibitory concentration (MIC) by 4- to 32-fold. Mechanistic analysis revealed that the synergistic effect arises from enhanced bacterial membrane permeation and concurrent inhibition of the resistance-nodulation-division (RND) efflux pump by quercetin, which lead in the increase in intracellular TGC levels by high‑performance liquid chromatography (HPLC) detection. Furthermore, metabolomics revealed significant perturbations in aminoacyl-tRNA biosynthesis along with significant perturbations in amino acid metabolism, consistent with TGC-induced translational arrest and elevated intracellular drug accumulation. In murine models of pulmonary infection, the TGC and Qu combination exhibited antibacterial efficacy. Collectively, our findings reveal a promising alternative therapeutic strategy for combating MDR A. baumannii infections.