Drug Design, Development and Therapy (Mar 2023)
Antimicrobial Peptide Cec4 Eradicates Multidrug-Resistant Acinetobacter baumannii in vitro and in vivo
Abstract
Jian Peng,1– 3,* Yue Wang,3,* Zhaoyin Wu,3 Chengju Mao,3 Lu Li,1,2 Huijun Cao,4 Zhilang Qiu,3 Guo Guo,3,5 Guiyou Liang,4,5 Feng Shen1,2 1Department of Intensive Care Unit, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 2Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 3Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, Cellular Immunotherapy Engineering Research Center of Guizhou Province, School of Biology and Engineering/School of Basic Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China; 4Department of Cardiac Surgery, the affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550009, People’s Republic of China; 5Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, 550025, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Shen; Guiyou Liang, Email [email protected]; [email protected]: Acinetobacter baumannii has become a major difficulty in the treatment of bacteria-associated infection. The previously reported antimicrobial peptide Cec4 exhibited good and stable activity against A. baumannii in vitro, but the mechanisms and effects in vivo are elusive.Methods: The effects of Cec4 on bacterial membrane permeability, membrane potential and bacterial reactive oxygen species were measured. The cell membrane localization of antimicrobial peptides was studied by fluorescence labelling. The ability of bacteria to develop resistance to antimicrobial peptides was studied by continuous induction, and transcriptome difference was analysed. The in vivo toxicity of Cec4 against nematodes and mice was studied, and the in vivo therapeutic potential of Cec4 against A. baumannii was assessed.Results: Cec4 effectively cleared multidrug-resistant A. baumannii by altering bacterial cell membrane permeability, changing bacterial cell membrane polarity, and increasing bacterial intracellular reactive oxygen species. Cec4 affected the expression of the secretion system, outer membrane, and efflux pump genes of A. baumannii. In addition, the bacteria did not acquire stable drug-resistant ability. Cec4 at 1.024 mg/mL did not affect the proliferation of HeLa and HepG2 cells, and Cec4 at 45 mg/kg had little effect on the mortality of Caenorhabditis elegans, even the liver and kidney tissues of mouse. Most importantly, Cec4 could effectively improve the survival rates and reduce the bacterial load of various tissues in the mouse model of infection.Conclusion: In conclusion, Cec4 can damage the cell membrane of bacteria, and the bacteria is not easy to produce resistance to Cec4. Besides, Cec4 has good potential for the treatment of multidrug-resistant A. baumannii infections.Keywords: antimicrobial peptide, A. baumannii, sepsis, skin infection, drug safety
