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 and , 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 (Code no. YFJ-36) with a new thioether linker. exhibited superior and broad-spectrum in vitro antibacterial activity, especially against and , compared with cefiderocol. Potent in vivo efficacy was observed in a murine systemic infection model. Furthermore, the physicochemical stability of in fluid medium at pH 6-8 was enhanced. also reduced potential the risk of allergy owing to the quaternary ammonium linker. The improved properties of supported its further research and development.