The worrying issue of antibiotic resistance in pathogenic bacteria is aggravated by the scarcity of novel therapeutic agents. Antibiotic adjuvants offer a promising solution due to their cost-effectiveness and high efficacy in addressing this issue, such as the β-lactamase inhibitor sulbactam (a β-lactam adjuvant) and the dihydrofolate reductase inhibitor trimethoprim (a sulfonamide adjuvant). This study aimed to discover potential adjuvants for tetracyclines from a list of previously approved drugs to restore susceptibility to Escherichia coli carrying the tetA gene. We have screened guanethidine, a compound from the Chinese pharmacopoeia, which effectively potentiates the activity of tetracyclines by reversing resistance in tetA-positive Escherichia coli, enhancing its antibacterial potency, and retarding the development of resistance. Guanethidine functions via the inhibition of the TetA efflux pump, thereby increasing the intracellular concentration of tetracyclines. Our findings suggest that guanethidine holds promise as an antibiotic adjuvant.
