AaeAP2a, a Scorpion-Derived Antimicrobial Peptide, Combats Carbapenem-Resistant Acinetobacter baumannii via Membrane Disruption and Triggered Metabolic Collapse

Weiyu Luo^1,2,3,4Liuwei Zhang^1,4Haolei Gao^1,4Huiying Li^1,4Xiaofeng Li^1,4Yuliang Wen^1,4Huarun Sun^1,4Bolin Hang^1,4Longfei Zhang^1,4Wei Zhang^1,4Xuehan Liu^1,4Ruibiao Wang^1,4Bo Wen^1,4Jiyuan Shen^1,4Chunling Zhu^1,4Yueyu Bai¹Lei Wang^1,4*Ke Ding^1,5*Jianhe Hu^1,4*

• ¹Henan Institute of Science and Technology, Xinxiang, China
• ²Postdoctoral Research Base, Henan Institute of Science and Technology, Xinxiang, China
• ³Postdoctoral Research Base, College of Veterinary Medicine, Henan Agricultural University, Zhengzhou, China
• ⁴Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou, China
• ⁵Laboratory of Functional Microbiology and Animal Health, Henan University of Science and Technology, Luoyang, China

Carbapenem-resistant Acinetobacter baumannii (CRAB) poses a significant global health challenge owing to its high mortality rates and widespread antibiotic resistance. While the clinical utility of last-resort antibiotics, such as colistin, remains limited. Consequently, developing novel antimicrobial agents is imperative. Antimicrobial peptides have emerged as promising candidates against multidrug-resistant pathogens. Animal venom constitutes a rich reservoir of bioactive peptides. Herein, we report a synthetic analog AaeAP2a derived from the scorpion peptide AaeAP2, which exhibits potent antibacterial activity against CRAB and a significant inhibitory effect on biofilm formation. Moreover, AaeAP2a maintains high stability under a broad range of stressful physicochemical conditions and exhibits promising biocompatibility in vitro. Mechanistically, AaeAP2a disrupts bacterial membrane integrity, increases membrane permeability, reduces the NAD+/NADH ratio, dissipates the proton motive force, decreases ATP production, and induces reactive oxygen species and hydroxyl radical accumulation. Moreover, in a mouse model of peritonitis-associated sepsis, AaeAP2a treatment enhanced survival rates and reduced bacterial burdens in key organs. These findings underscore the potential of AaeAP2a as a promising therapeutic agent for CRAB infections, offering novel strategies for addressing antimicrobial resistance.