Discovery of New Teraryl γ-Lactam Derivatives as Potent Antibacterial Agents In Vitro and In Vivo through Dual Cell Wall–Membrane Inhibitions

Antimicrobial resistance threatens global public health, urgently requiring new antibiotics. Herein, we report a novel antibacterial scaffold with a 1,2,4-oxadiazole teraryl moiety and γ-lactam fragment via bacteria-based phenotypic screening. Diversified modifications of its four sites yielded 42 derivatives, and comprehensive SAR analysis against multidrug-resistant "superbugs" identified lead compound 8c. 8c exhibits excellent activity against drug-resistant Gram-positive bacteria (e.g., MRSA, VISA, VRE), 4-32-fold more potent than ciprofloxacin and meropenem. 8c shows rapid bactericidal activity, a low propensity to induce resistance, and a moderate safety profile. Mechanistically, 8c inhibits peptidoglycan biosynthesis by targeting the Lipid II cycle and disrupts membrane homeostasis via enhanced permeability and induced hyperpolarization, with this dual action validated by proteomic and lipidomic analyses. It also has excellent liver microsomal stability, favorable in vivo pharmacokinetics, and potent in vivo anti-MRSA efficacy. This novel scaffold is a promising addition to the antibiotic arsenal and warrants further development.