期刊
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
卷 158, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejps.2020.105665
关键词
Antimicrobial peptides; Cell selectivity; Antibiotic adjuvant; Rifampin; Rifampin-resistant Escherichia coli; Gram-negative bacteria
资金
- National Natural Science Foundation of China [81773564]
- Key Science and Technology Foundation of Gansu Province [17YF1FA125]
- Key Research Development Programs of the Provincial Science & Technology Research Projects of Gansu Province [18YF1FA109]
Newly designed peptides with excellent bioactivity, modest cell toxicity, low resistance tendency, and moderate stability have been developed through amino acid substitution and peptide truncation. These peptides demonstrate synergy or additive effects against Gram-negative bacteria when combined with conventional antibiotics, showing promise as antibiotic alternatives to tackle the risk of drug-resistant Gram-negative bacteria.
The increasing prevalence of antibiotic resistance in Gram-negative bacteria calls for the discovery of novel effective therapeutic strategies urgently. Mastoparan-C (MP-C), a typical cationic alpha-helical antimicrobial peptide, possesses remarkable broad-spectrum antimicrobial activity. However, its high cytotoxicity toward normal mammalian cells precludes it for further development. In this study, to avoid non-specific membrane lysis and investigate the structure-function relationships of each amino acid of MP-C, a series of new MP-C analogs were rationally designed by amino acid substitution and peptide truncation. Three potential newly designed peptides L(1)G, L(7)A, and L(1)GA(5)K with excellent bioactivity, modest cell toxicity, low resistance tendency, and moderate stability to physiological salts and proteases were screened out. Moreover, the newly designed peptides showed synergy or additive effects against Gram-negative bacteria, when they combined with conventional antibiotics gentamicin, rifampin, and polymyxin B. The results from the time-kill kinetics, outer/inner membrane permeabilization, scanning electron microscope (SEM), and flow cytometry demonstrated that the newly designed peptides could kill bacteria rapidly by membrane destruction and intracellular contents leakage in a concentration and time-dependent manner. Specifically, the most cell-selective peptide L(1)GA(5)K exhibited potent antimicrobial activity against rifampin-resistant E. coli (RRE) and prevented the emergence of rifampin resistance in Enterobacter. Besides, L(1)GA(5)K was capable of reversing rifampin resistance in RRE through the outer membrane permeabilization when used in combination with rifampin. Collectively, our results suggested that the newly designed peptides are hopeful antibiotic alternatives, and the usage of them as an adjuvant to prevent and reverse antibiotic resistance is a promising strategy for tackling the risk of drug-resistant Gram-negative bacteria.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据