Recent discoveries of propyl gallate restore the antibacterial effect of tigecycline against tet(X4)-positive Escherichia coli.

Propyl gallate (PG), an approved food additive, can be added to different foods and drugs to provide health benefits with minimal danger. However, no clinical application of PG as an antibacterial agent for the treatment of antimicrobial resistance (AMR) has been documented. The aim of this study was to elucidate the effects and mechanisms by which PG inhibits the activity of Tet(X4). Enzyme activity inhibition assay, antimicrobial tests, scanning electron microscopy (SEM) assay, molecular docking and dynamics simulation assays, and animal infection models were used to confirm the synergistic efficacy and mechanism. Here, we found that PG efficiently inhibited Tet(X4) enzyme activity (IC50 = 34.83 μg/mL) while affecting the expression of tet(X4). PG has a synergistic effect with tigecycline (fractional inhibitory concentration index (FICI) < 0.5) against tet(X4)-positive Escherichia coli (E. coli) isolates of animal origin. The survival rates of G. mellonella larvae and the mouse systemic infection model increased by 60 % and 39 %, respectively. The combination of PG and tigecycline showed remarkable treatment benefits in terms of the bacterial load and inflammatory factors in mice. Our results indicate that PG is a valuable adjuvant with tetracyclines and can be considered to address the inevitable infection caused by tet(X4)-positive bacteria, which is a feasible way to extend the lifespan of existing antibiotics.