An in vitro comparative study of cefiderocol, siderophore-aztreonam and siderophore-daptomycin conjugates against select gram-negative bacteria.

Multidrug-resistant (MDR) Gram-negative bacteria pose significant therapeutic challenges due to their protective outer membranes and evolving resistance mechanisms. Exploiting bacterial iron uptake pathways via siderophore-antibiotic conjugates offers a promising strategy to enhance antibiotic efficacy. Here we synthesized siderophore-aztreonam, and siderophore-daptomycin conjugates and compared their activity to that of cefiderocol against select Gram-negative pathogens, including MDR Acinetobacter baumannii and Pseudomonas aeruginosa. Our in vitro studies demonstrated that siderophore conjugates exhibit comparable or superior antimicrobial activity to, with daptomycin conjugates notably retaining efficacy over extended periods. These findings suggest that conjugation with iron chelators that closely mimic natural siderophores can improve antibiotic delivery and activity, providing complementary options to existing therapies for multidrug-resistant Gram-negative infections.