Chemical Biology and Drug Design
Chemical Biology and Drug Design
5 years ago

Novel antimicrobial peptide CPF-C1 analogs with superior stabilities and activities against multidrug-resistant bacteria

Novel antimicrobial peptide CPF-C1 analogs with superior stabilities and activities against multidrug-resistant bacteria
Rui Wang, Xianxing Jiang, Xiaokang Miao, Bangzhi Zhang, Jing Li, Yao Li, Zhibin Yan, Sisi Li, Junqiu Xie, Wenle Yang, Lingyun Mou, Qian Zhao
As numerous clinical isolates are resistant to most conventional antibiotics, infections caused by multidrug-resistant bacteria are associated with a higher death rate. Antimicrobial peptides show great potential as new antibiotics. However, a major obstacle to the development of these peptides as useful drugs is their low stability. To overcome the problem of the natural antimicrobial peptide CPF-C1, we designed and synthesized a series of analogs. Our results indicated that by introducing lysine, which could increase the number of positive charges, and by introducing tryptophan, which could increase the hydrophobicity, we could improve the antimicrobial activity of the peptides against multidrug-resistant strains. The introduction of d-amino acids significantly improved stability. Certain analogs demonstrated antibiofilm activities. In mechanistic studies, the analogs eradicated bacteria not just by interrupting the bacterial membranes, but also by linking to DNA, which was not impacted by known mechanisms of resistance. In a mouse model, certain analogs were able to significantly reduce the bacterial load. Among the analogs, CPF-9 was notable due to its greater antimicrobial potency in vitro and in vivo and its superior stability, lower hemolytic activity, and higher antibiofilm activity. This analog is a potential antibiotic candidate for treating infections induced by multidrug-resistant bacteria. To improve the stability of the natural antimicrobial peptide CPF-C1, a series of analogs were designed and synthesized by chemical modification. Among the analogs, CPF-9 was notable due to its greater antimicrobial potency in vitro and in vivo and its superior stability, lower hemolytic activity, and higher antibiofilm activity. It killed bacteria not only by disrupting the bacterial membranes but also by binding to DNA. This analog is a potential antibiotic candidate for treating infections induced by multidrug-resistant bacteria.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12988

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