Abaucin analogs sharpen lipoprotein-transport inhibition and in vivo protection against resistant A. baumannii
- Thirty analogs of the deep-learning-derived antibiotic abaucin were made to map SAR against carbapenem-resistant Acinetobacter baumannii.
- The spirocyclic core, linker length and aromatic substituents emerged as key determinants of activity.
- Lead compound 28 inhibited the LolF/D lipoprotein transport complex more strongly and showed rapid bactericidal action with little spontaneous resistance; paired with a membrane permeabilizer, it fully protected mice in a sepsis model and appeared tolerable.
💡 Points
LolCDE is a rare, genuinely tractable Gram-negative target, and a spirocyclic core with tunable linker length is a scaffold I can actually iterate on. But the needed permeabilizer co-dose tells me the lead alone still can't clear the outer membrane in vivo. I'd want a permeabilizer-free MIC shift and PK before believing the sepsis protection.