Structure-activity relationship (SAR) studies of abaucin derivatives targeting the lipoprotein transport system in Acinetobacter baumannii.

Carbapenem-resistant A. baumannii (CRAB) has been classified by the World Health Organization (WHO) as a critical priority antibiotic-resistant pathogen, making it one of the highest priorities for global antibiotic development. In 2023, abaucin, a narrow-spectrum antibiotic selectively targeting the lipoprotein transport system in Acinetobacter baumannii, was identified through deep learning-based screening. In this study, we designed and synthesized 30 abaucin derivatives to further explore the structure-activity relationship (SAR). SAR analysis revealed that the spirocyclic scaffold, linker length and aromatic substituents played critical roles. Lead compound 28 was identified with markedly improved inhibition of the LolF/D complex and antibacterial activity against A. baumannii (MIC = 0.5 μg/mL). Further studies demonstrated that compound 28 exhibited rapid and complete bactericidal kinetics and low prevalence of spontaneous drug resistance. Combination of compound 28 with a membrane permeabilizer PMB exhibited 100% protection in a mouse sepsis model. Compound 28 also showed satisfactory safety properties. Collectively, these findings highlight compound 28 as a promising lead compound for the development of novel antibacterial agents against A. baumannii.