A novel chemosynthetic peptide with ß-sheet motif efficiently kills Klebsiella pneumoniae in a mouse model

Abstract

Shirui Tan,1,2,* Changpei Gan,1,3,* Rongpeng Li,1 Yan Ye,1 Shuang Zhang,1,3 Xu Wu,1 Yi Yan Yang,4 Weimin Fan,5 Min Wu11Department of Basic Sciences, School of Medicine and Health Sciences University of North Dakota, Grand Forks, ND, USA; 2Laboratory of Biochemistry and Molecular Biology, School of Life Sciences, Yunnan University, Kunming, People’s Republic of China; 3State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 4Institute of Bioengineering and Nanotechnology, The Nanos, Singapore; 5Program of Innovative Cancer Therapeutics, First Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Klebsiella pneumoniae (Kp) is one of the most common pathogens in nosocomial infections and is increasingly becoming multiple drug resistant. However, the molecular pathogenesis of Kp in causing tissue injury and dysregulated host defense remains elusive, further dampening the development of novel therapeutic measures. We have previously screened a series of synthetic antimicrobial beta-sheet forming peptides and identified a peptide (IRIKIRIK; ie, IK8L) with a broad range of bactericidal activity and low cytotoxicity in vitro. Here, employing an animal model, we investigated the antibacterial effects of IK8L in acute infection and demonstrated that peritoneal injection of IK8L to mice down-regulated inflammatory cytokines, alleviated lung injury, and importantly, decreased mortality compared to sham-injected controls. In addition, a math model was used to evaluate in vivo imaging data and predict infection progression in infected live animals. Mechanistically, IK8L can kill Kp by inhibiting biofilm formation and modulating production of inflammatory cytokines through the STAT3/JAK signaling both in vitro and in vivo. Collectively, these findings reveal that IK8L may have potential for preventing or treating Kp infection.Keywords: bacterial pathogenesis, inflammatory cytokines, infectious diseases, bactericidal activity, antimicrobial peptides, STAT3/JAK signaling transduction