Designed symmetrical β-hairpin peptides for treating multidrug-resistant salmonella typhimurium infections

• DOI: 10.1016/j.ejmech.2022.114769
• Publication Date: 2022-09-15T06:57:37Z
• Authors: Zhi Ma; Dong Zhang; Ziyi Cheng; Yandong Niu; Liangyu Kong; Zhaoxin Lu; Xiaomei Bie
• Keywords: Salmonella typhimurium; Lipopolysaccharides; 0303 health sciences; 03 medical and health sciences; Salmonella Infections; Animals; Humans; Peptides; Anti-Bacterial Agents; 3. Good health

The rapid emergence and prevalence of multidrug-resistant salmonellosis lack effective therapies, which causes epidemic health problems and stimulates the development of antimicrobials with novel modes of action. In this research, 10 short symmetrical β-hairpin peptides are synthesized by combining the β-turn of Leucocin-A with recurring hydrophobic and cationic amino acid sequences. Those designed peptides exhibited potent antibacterial activities against drug-susceptible and drug-resistant Salmonella. One of the 10 peptides, WK2 ((WK)2CTKSGC(KW)2), displayed best cell selectivity towards Salmonella cells over macrophages and erythrocytes in a co-culture model. Fluorescent measurements and microscopic observations reflected that WK2 exerted its antimicrobial activity through a membrane-lytic mechanism. Moreover, the β-hairpin peptides can bind to endotoxin (LPS) and suppress the production of LPS-induced proinflammatory cytokines in RAW264.7 cells, indicating as a potent anti-inflammatory activity. The preliminary in vivo studies can also demonstrate that WK2 decreased loads of Salmonella in the liver and spleen, mitigated Salmonella-caused inflammation and maintained the integrity of intestinal mucosal surfaces. Ultimately, the results highlight that WK2 is a promising therapeutic agent to prevent multidrug-resistant S. Typhimurium infections in humans and animals.