A Broad-Spectrum Abietane Diterpenoid Derivative that Targets Lipid II Cycle and Bacterial Membrane to Combat Multidrug Resistance

The escalating threat of drug-resistant superbugs has urgently necessitated the development of antibiotics with novel scaffolds and mechanisms. Herein, we rationally designed and synthesized novel abietane diterpenoid derivatives from carnosic acid (CA) inspired by the "amine/guanidine" modification strategy. Most derivatives designed exhibited greater activities than CA and even vancomycin (∼2-64-fold). The optimized <b>4c</b> demonstrated ultrabroad-spectrum activity against MRSA, VRE, CRAB, and mycobacteria, coupled with desirable properties of rapid bactericidal ability, low resistance development propensity, and good safety profile. Mechanistic studies first revealed a novel independent and synergistic "cell wall-membrane" dual inhibitory mechanism, respectively, via interfering with bacterial lipid II cycle and inducing membrane permeabilization and depolarization. Subsequent <i>in vivo</i> studies elucidated that <b>4c</b> demonstrated favorable efficacy in zebrafish and mouse infection models. Collectively, these findings highlight the antimicrobial potential of abietane diterpenoids derived from CA and identify <b>4c</b> as a promising drug candidate against drug-resistant bacterial infections.