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

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 beta-hairpin peptides are synthesized by combining the beta-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)(2)CTKSGC(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 beta-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.

Automated summary

The study synthesized a series of 10 short symmetrical beta-hairpin peptides, among which WK2 displayed the best selectivity towards Salmonella cells and exerted its antimicrobial activity through a membrane-lytic mechanism. Additionally, WK2 showed anti-inflammatory activity by suppressing the production of proinflammatory cytokines and demonstrated therapeutic effects against Salmonella infections in vivo.