Modular Synthesis of Aerobactin-Aztreonam Conjugates with Enhanced Activity against Hypervirulent Klebsiella pneumoniae.

A modular strategy enabled controlled mono- and difunctionalization of aerobactin and late-stage attachment of alkyne-bearing payloads by CuAAC. Application to aztreonam afforded the first aerobactin-antibiotic conjugates. Monovalent conjugate 3b showed superior activity against hypervirulent Klebsiella pneumoniae KPN234 (MIC = 0.031 μM), a 16-fold improvement over aztreonam. Competition and iron-dependent activity studies supported aerobactin-pathway-dependent delivery, establishing aerobactin as a viable antibacterial delivery scaffold.