Discovery of YFJ-36: Design, Synthesis, and Antibacterial Activities of Catechol-Conjugated β‑Lactams against Gram-Negative Bacteria

Cefiderocol is the first approved catechol-conjugated
cephalosporin
against multidrug-resistant Gram-negative bacteria, while its application
was limited by poor chemical stability associated with the pyrrolidinium
linker, moderate potency against Klebsiella pneumoniae and Acinetobacter baumannii, intricate
procedures for salt preparation, and potential hypersensitivity. To
address these issues, a series of novel catechol-conjugated derivatives
were designed, synthesized, and evaluated. Extensive structure-activity
relationships and structure-metabolism relationships (SMR) were conducted,
leading to the discovery of a promising compound 86b (Code
no. YFJ-36) with a new thioether linker. 86b exhibited
superior and broad-spectrum in vitro antibacterial activity, especially
against A. baumannii and K. pneumoniae, compared with cefiderocol. Potent
in vivo efficacy was observed in a murine systemic infection model.
Furthermore, the physicochemical stability of 86b in
fluid medium at pH 6–8 was enhanced. 86b also
reduced potential the risk of allergy owing to the quaternary ammonium
linker. The improved properties of 86b supported its
further research and development.