Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, PR China.
Chemistry and Chemical Engineering Guangdong Laboratory, Guangdong, PR China.
Nat Commun. 2023 Sep 1;14(1):5311. doi: 10.1038/s41467-023-40828-3.
The rapid emergence of antimicrobial resistance (AMR) pathogens highlights the urgent need to approach this global burden with alternative strategies. Cefiderocol (Fetroja®) is a clinically-used sideromycin, that is utilized for the treatment of severe drug-resistant infections, caused by Gram-negative bacteria; there is evidence of cefiderocol-resistance occurring in bacterial strains however. To increase the efficacy and extend the life-span of sideromycins, we demonstrate strong synergisms between cefiderocol and metallodrugs (e.g., colloidal bismuth citrate (CBS)), against Pseudomonas aeruginosa and Burkholderia cepacia. Moreover, CBS enhances cefiderocol efficacy against biofilm formation, suppresses the resistance development in P. aeruginosa and resensitizes clinically isolated resistant P. aeruginosa to cefiderocol. Notably, the co-therapy of CBS and cefiderocol significantly increases the survival rate of mice and decreases bacterial loads in the lung in a murine acute pneumonia model. The observed phenomena are partially attributable to the competitive binding of Bi to cefiderocol with Fe, leading to enhanced uptake of Bi and reduced levels of Fe in cells. Our studies provide insight into the antimicrobial potential of metallo-sideromycins.
抗菌药物耐药性（AMR）病原体的迅速出现凸显出迫切需要采用替代策略来应对这一全球性负担。头孢地尔（Fetroja®）是一种临床应用的铁载体抗生素，用于治疗由革兰氏阴性菌引起的严重耐药性感染；然而，已经有证据表明细菌菌株中存在头孢地尔耐药性。为了提高疗效并延长铁载体抗生素的寿命，我们证明了头孢地尔与金属药物（例如胶体柠檬酸铋（CBS））之间具有很强的协同作用，可对抗铜绿假单胞菌和洋葱伯克霍尔德菌。此外，CBS 增强了头孢地尔对生物膜形成的疗效，抑制了铜绿假单胞菌的耐药性发展，并使临床分离的耐药铜绿假单胞菌重新对头孢地尔敏感。值得注意的是，CBS 和头孢地尔的联合治疗显著提高了急性肺炎小鼠模型的存活率，并降低了肺部的细菌负荷。观察到的现象部分归因于 Bi 与 Fe 对头孢地尔的竞争性结合，导致 Bi 的摄取增加和细胞内 Fe 水平降低。我们的研究为金属铁载体抗生素的抗菌潜力提供了新的见解。
