Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance

Chenyuan Wang, Yushan Xia, Runming Wang, Jingru Li, Chun-Lung Chan, Richard Yi-Tsun Kao, Patrick H. Toy, Pak-Leung Ho, Hongyan Li () and Hongzhe Sun ()
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Chenyuan Wang: The University of Hong Kong
Yushan Xia: The University of Hong Kong
Runming Wang: The University of Hong Kong
Jingru Li: The University of Hong Kong
Chun-Lung Chan: The University of Hong Kong
Richard Yi-Tsun Kao: The University of Hong Kong
Patrick H. Toy: The University of Hong Kong
Pak-Leung Ho: The University of Hong Kong
Hongyan Li: The University of Hong Kong
Hongzhe Sun: The University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40828-3

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