Abstract

Pathogenic bacteria scavenge ferric iron from the host for survival and proliferation using small-molecular chelators, siderophores. Siderophore-antibiotic conjugates, also called sideromycins, which were designed based on a “Trojan Horse” strategy wherein features enabled active uptake to bypass the Gram-negative cell wall, have been expected to be an efficient weapon for multidrug resistant strains caused infections in the clinic1,2. Cefiderocol, a cephalosporin sideromycin drug for Gram‐negative bacterial infections, was approved by FDA recently.3 Herein, the combination of bismuth(III) and cefiderocol is introduced to enhance the antimicrobial activity against P. aeruginosa. The MIC of cefiderocol can be reduced 64-fold after combination with bismuth(III) drugs, indicative of a synergy between sideromycin and bismuth compounds against Pseudomonas aeruginosa strains. The uptake competition between iron(III) and bismuth(III) is considered as one of the reasons to this synergistic effect. Such a strategy enhances cefiderocol efficacy and suppresses the resistance development in P. aeruginosa, suggesting metallo-sideromycin as a novel strategy to cope with antimicrobial resistance (AMR) crisis. 

We thank the Research Grants Council (RGC) and Innovative Technology Commission of Hong Kong, the University of Hong Kong and Norman & Celia Yip Foundation for financial support.

References

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