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 4c 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 in vivo studies elucidated that 4c demonstrated favorable efficacy in zebrafish and mouse
infection models. Collectively, these findings highlight the antimicrobial
potential of abietane diterpenoids derived from CA and identify 4c as a promising drug candidate against drug-resistant bacterial
infections.