Inosine reverses multidrug resistance in Gram-negative bacteria carrying mobilized RND-type efflux pump gene cluster <i>tmexCD-toprJ</i>

TMexCD1-TOprJ1, a mobilized resistance-nodulation-division-type efflux pump, confers phenotypic resistance to multiple classes of antibiotics. Nowadays, <i>tmexCD-toprJ</i> has disseminated among diverse species of clinical pathogens, exacerbating the need for novel anti-infective strategies. In this study, we report that <i>tmexCD1-toprJ1</i>-negative and -positive bacteria exhibit significantly different metabolic flux and characteristics, especially in purine metabolism. Intriguingly, the addition of inosine, a purine metabolite, effectively restores the antibacterial activity of tigecycline by promoting antibiotic uptake. Our findings highlight the correlation between bacterial mechanism and antibiotic resistance, and offer a distinct approach to overcome <i>tmexCD-toprJ</i>-mediated multidrug resistance.