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.