Department of Chemistry, State Key Laboratory of Synthetic Chemistry, CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong, China.
Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, Netherlands.
Nat Microbiol. 2024 Oct;9(10):2600-2613. doi: 10.1038/s41564-024-01807-6. Epub 2024 Sep 18.
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.
铜绿假单胞菌感染难以治疗，因为抗生素耐药性迅速发展。已经使用的药物联合使用是开发新抗生素来对抗抗药性细菌的替代方法。在这里，我们证明基于铋的药物（次水杨酸铋、胶体柠檬酸铋）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药耐药铜绿假单胞菌，并且不会诱导抗生素耐药性的产生。铋通过与铜绿假单胞菌的铁载体结合来破坏铁稳态。在细胞内，铋通过抑制电子传递链、耗散质子动力势和破坏含铁硫簇的酶（包括呼吸复合物）来抑制外排泵的活性。结果，铋促进了抗生素在细菌内的积累，增强了其疗效。联合治疗在体外菌血症模型中表现出强大的抗菌功效和低毒性，并提高了体内小鼠肺部感染模型中小鼠的存活率。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使用来对抗铜绿假单胞菌感染的潜力。
