May 2024
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5 Reads
European Journal of Medicinal Chemistry
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May 2024
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5 Reads
European Journal of Medicinal Chemistry
April 2024
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24 Reads
European Journal of Medicinal Chemistry
March 2024
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25 Reads
Journal of Medicinal Chemistry
March 2024
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32 Reads
European Journal of Medicinal Chemistry
February 2024
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16 Reads
European Journal of Medicinal Chemistry
June 2023
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28 Reads
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7 Citations
Journal of Medicinal Chemistry
The ongoing emergence of antibiotic-resistant pathogens had been dramatically stimulating and accelerating the need for new drugs. PE2 is a kind of cyclic lipopeptide with broad-spectrum antimicrobial activity. Herein, its structure-activity relationship was systematically investigated by employing 4 cyclic analogues and 23 linear analogues for the first time. The screened linear analogues 26 and 27 bearing different fatty acyls at N-termini and a Tyr residue at the 9th position had superior potency compared to the cyclic analogues and showed equivalent antimicrobial activity compared with PE2. Notably, 26 and 27 exhibited significant ability against multidrug-resistant bacteria, favorable resistance to protease, excellent performance against biofilm, low drug resistance, and high effectiveness against the mice pneumonia model. The antibacterial mechanisms of PE2 and linear derivatives 26 and 27 were also preliminarily explored in this study. As described above, 26 and 27 are promising antimicrobial candidates for the treatment of infections associated with drug-resistant bacteria.
October 2022
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28 Reads
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7 Citations
Acta Biomaterialia
The increasingly severe bacterial resistance worldwide pushes people to discover and design potential antibacterial drugs unavoidably. In this work, a series of short, mirror-symmetric peptides were designed and successfully synthesized, centered on “RRR” and labeled with hydrophobic amino acids at both ends. Based on the structure-activity relationship analysis, LWWR (LWWRRRWWL-NH2) was screened as a desirable mirror-symmetric peptide for further study. As expected, LWWR displayed broad-spectrum antibacterial activity against the standard bacteria and antibiotic-resistant strains. Undoubtedly, the high stability of LWWR in a complex physiological environment was an essential guarantee to maximizing its antibacterial activity. Indeed, LWWR also exhibited a rapid bactericidal speed and a low tendency to develop bacterial resistance, based on the multiple actions of non-receptor-mediated membrane actions and intra-cellular mechanisms. Surprisingly, although LWWR showed similar in vivo antibacterial activity compared with Polymyxin B and Melittin, the in vivo safety of LWWR was far higher than that of them, so LWWR had better therapeutic potential. In summary, the desirable mirror-symmetric peptide LWWR was promised as a potential antibacterial agent to confront the antibiotics resistance crisis. Statement of Significance Witnessing the growing problem of antibiotic resistance, a series of short, mirror-symmetric peptides based on the symmetric center “RRR” and hydrophobic terminals were designed and synthesized in this study. Amongst, LWWR (LWWRRRWWL-NH2) presented broad-spectrum antibacterial activity both in vitro and in vivo due to its multiple mechanisms and good stability. Meanwhile, the low drug resistance and toxicity of LWWR also suggested its potential for clinical application. The findings of this study will provide some inspiration for the design and development of potential antibacterial agents, and contribute to the elimination of bacterial infections worldwide as soon as possible.
... AMPs have also been isolated from bacteria, e.g., Zhang et al. aimed to simplify the structure of the AMP PE2 isolated from the endospore-forming, facultative anaerobic bacterium Paenibacillus ehimensis. Linear analogues of AMP PE2, numbered 26 and 27, showed significant activity against both MDR bacteria in vitro as well as in a mouse pneumonia model [127]. A different AMP, 'YS12 ′ , was derived from Bacillus velezensis strain CBSYS12 via the Korean food kimchi. ...
June 2023
Journal of Medicinal Chemistry
... Additionally, Zhang et al. designed a series of mirror-symmetric peptides centered on "RRR" and labeled them with hydrophobic amino acids at both ends (Fig. 8C). The target peptide LWWR (LWWRRRWWL-NH 2 ) exhibited broadspectrum antibacterial activity and high stability in physiological salt environments [117]. ...
October 2022
Acta Biomaterialia