3 results on '"Bao, Hexin"'
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2. Newly designed antimicrobial peptides with potent bioactivity and enhanced cell selectivity prevent and reverse rifampin resistance in Gram-negative bacteria.
- Author
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Zhu, Ningyi, Zhong, Chao, Liu, Tianqi, Zhu, Yuewen, Gou, Sanhu, Bao, Hexin, Yao, Jia, and Ni, Jingman
- Subjects
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PEPTIDE antibiotics , *ANTIMICROBIAL peptides , *GRAM-negative bacteria , *RIFAMPIN , *POLYMYXIN B , *SCANNING electron microscopes , *POLYMYXIN , *DRUG resistance in bacteria - Abstract
• The first study to elucidate the structure-activity–toxicity relationships of Mastoparan-C. • Three potential antimicrobial peptides L 1 G, L 7 A, and L 1 GA 5 K are obtained by optimizing the sequence of Mastoparan-C. • L 1 G, L 7 A, and L 1 GA 5 K exerted excellent antimicrobial activity, enhanced cell selectivity, and low resistance tendency. • L 1 GA 5 K exhibited the capability to prevent the emergence of rifampin resistance in Gram-negative bacteria. • L 1 GA 5 K reversed rifampin resistance in Gram-negative bacteria related to the outer membrane permeabilization. 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 α-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. Image, graphical abstract [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
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3. Effect of N-methylated and fatty acid conjugation on analogs of antimicrobial peptide Anoplin.
- Author
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Liu, Tianqi, Zhu, Ningyi, Zhong, Chao, Zhu, Yuewen, Gou, Sanhu, Chang, Linlin, Bao, Hexin, Liu, Hui, Zhang, Yun, and Ni, Jingman
- Subjects
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ANTIMICROBIAL peptides , *FATTY acids , *BACTERIAL cell membranes , *AMINO acids , *POLYMYXIN B , *PEPTIDES , *ANTIMICROBIAL polymers - Abstract
With the increment of drug-resistant bacteria and the slow development of novel antibiotics, antimicrobial peptides have gained increasing attention as a potential antibiotic alternative. They not only displayed a broad-spectrum antimicrobial activity but also were difficult to induce resistance development because of their unique membrane-lytic activity. Herein, to improve the limitations of Anoplin, the N-methyl amino acids were first used to replace the amino acids of Anoplin at sensitive enzymatic cleave sites (Leu, Ile, Lys and Arg). Afterward, the N-methylated analogs M3.6/M4.7/M5.7 with high stability were screened out and further modified by N-terminal fatty acid conjugation to develop new antimicrobial peptide analogs with both potent antimicrobial activity and high proteolytic stability, and 12 new Anoplin analogs Cn-M3.6/M4.7/M5.7 (n = 8,10,12,14) were designed and synthesized. Our results showed that compared with native Anoplin, the stability of these N-methylated lipopeptides against trypsin and chymotrypsin degradation were increased by 104–106 times. Besides, they still possessed potent antimicrobial activity under physiological salts and serum environment. Among them, the new designed analogs C12-M3.6/M4.7/M5.7 showed the optimal antimicrobial activity, synergy and additive effects were also observed when they were combined with traditional antibiotics polymyxin B, rifampin, and kanamycin. Moreover, they could effectively inhibit the formation of biofilms by P. aeruginosa and S. aureus. The antimicrobial mechanism studied revealed that these N-methylated lipopeptides could display a rapid bactericidal effect by destroying the bacterial cell membrane. Notably, no detectable resistance of these new designed peptides was developed after continuous cultured with E. coli for 20 passages. In summary, we have designed a new class of antimicrobial peptide analogs with potent antimicrobial activity and high proteolytic stability through N-methyl amino acids substitution and N-terminal fatty acid conjugation. This study also provides new ideas and methods for the modification of antimicrobial peptides in the future. Image, graphical abstract [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
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