Structure-activity relationship (SAR) studies of abaucin derivatives targeting the lipoprotein transport system in
Jiayi He1, Rui Teng1, Zhuyun Tang2
1State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Abstract:
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.
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