PDF(Pubmed)
Abstract：
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 Bi3+ to cefiderocol with Fe3+, leading to enhanced uptake of Bi3+ and reduced levels of Fe3+ in cells. Our studies provide insight into the antimicrobial potential of metallo-sideromycins.
摘要：
抗生素耐药性（AMR）病原体的迅速出现凸显了迫切需要通过替代策略来应对这一全球负担。Cefiderocol（Fetroja®）是临床上使用的西德霉素，用于治疗严重的耐药感染，由革兰氏阴性菌引起；然而，有证据表明细菌菌株中存在头孢地洛耐药性。为了提高效力，延长铁皮霉素的寿命，我们证明了头孢地洛和金属药物之间的强协同作用(例如，胶体柠檬酸铋（CBS）），对铜绿假单胞菌和洋葱伯克霍尔德菌。此外，CBS增强头孢地洛对抗生物膜形成的功效，抑制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对头孢地洛重新敏感。值得注意的是,在小鼠急性肺炎模型中,CBS和头孢地洛的联合治疗显著提高了小鼠的存活率并降低了肺中的细菌负荷.观察到的现象部分归因于Bi3与Fe3的头孢地洛竞争性结合，导致细胞中Bi3+的摄取增强和Fe3+的水平降低。我们的研究提供了对金属铁皮霉素抗菌潜力的见解。
