Pseudomonas aeruginosa infections are difficult to treat due to rapid development of antibiotic drug resistance. The synergistic combination of already-in-use drugs is an alternative to developing new antibiotics to combat antibiotic-resistant bacteria. Here we demonstrate that bismuth-based drugs (bismuth subsalicylate, colloidal bismuth subcitrate) in combination with different classes of antibiotics (tetracyclines, macrolides, quinolones, rifamycins and so on) can eliminate multidrug-resistant P. aeruginosa and do not induce development of antibiotic resistance. Bismuth disrupts iron homeostasis by binding to P. aeruginosa siderophores. Inside cells, bismuth inhibits the electron transport chain, dissipates the proton motive force and impairs efflux pump activity by disrupting iron–sulfur cluster-containing enzymes, including respiration complexes. As a result, bismuth facilitates antibiotic accumulation inside bacteria, enhancing their efficacy. The combination therapy shows potent antibacterial efficacy and low toxicity in an ex vivo bacteraemia model and increases the survival rate of mice in in vivo mouse lung-infection models. Our findings highlight the potential of bismuth-based drugs to be repurposed to combat P. aeruginosa infections in combination with clinically used antibiotics.

由于抗生素耐药性的迅速发展，铜绿假单胞菌感染难以治疗。已在使用的药物的协同组合是开发新抗生素以对抗抗生素耐药细菌的替代方案。在这里，我们证明了基于铋的药物（次水杨酸铋、胶体次柠檬酸铋）与不同类别的抗生素（四环素类、大环内酯类、喹诺酮类、利福霉素等）联合使用可以消除多重耐药性铜绿假单胞菌，并且不会诱导抗生素耐药性的发展。铋通过与铜绿假单胞菌铁载体结合来破坏铁稳态。在细胞内，铋通过破坏含铁硫簇的酶（包括呼吸复合物）来抑制电子传递链、消散质子动力并损害外排泵活性。因此，铋促进抗生素在细菌体内积累，从而提高其疗效。该联合疗法在离体菌血症模型中显示出有效的抗菌效果和低毒性，并在体内小鼠肺部感染模型中提高了小鼠的存活率。我们的研究结果强调了基于铋的药物与临床使用的抗生素联合用于对抗铜绿假单胞菌感染的潜力。