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Design, biological characteristics, and antibacterial mechanism of high therapeutic index antimicrobial peptides with PRRP as central axis

The Journal of Antibiotics volume 77, pages 170–181 (2024)Cite this article

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Abstract

As the important components of biological innate immunity, antimicrobial peptides (AMPs) were found in a variety of organisms including insects, plants, animals, bacteria, fungi, etc. However, high hemolytic activity, high toxicity, and poor stability of natural AMPs hinder serious their application as therapeutic agents. To overcome these problems, in this study we use PRRP as a central axis, and peptides were designed based on the sequence template XRRXXRXPRRPXRXXRRX-NH2, where X represents a hydrophobic amino acid like Phe (F), Ile (I), Val (V), and Leu (L). The designed peptides LR18, FR18, and IR18 showed effective antimicrobial activity against some Gram-positive bacteria and Gram-negative bacteria, low cytotoxicity to mammalian cells, and had a tendency to form α-helical structures in membrane-mimetic environments. Among them, peptide LR18 (X: L) showed the highest geometric mean average treatment index (GMTI = 42.7) against Gram-negative bacteria, and FR18 (X: L) showed the highest GMTI (22.86) against Gram-positive bacteria. LR18 and FR18 also showed better salt, temperature, pH, and trypsin stability. LR18 and FR18 exert their antimicrobial effects mainly through destroying bacteria cell membrane. Briefly, peptide LR18 and FR18 have the potential to serve as a therapeutic agent to reduce antibiotic resistance owing to its high therapeutic index and great stability.

Highlights

  • Introducing symmetry axis PRRP to the sequence of the typical α-helical antimicrobial peptides can improve their therapeutic index and stability.

  • The designed peptides LR18, FR18, and IR18 all have broad-spectrum and efficient antibacterial activity.

  • LR18 showed the highest average therapeutic index (GMTI = 42.7) against Gram-negative bacteria, and FR18 showed the highest (GMTI = 22.86) against Gram-positive bacteria.

  • Both the designed peptides LR18 and FR18 showed good thermal stability, pH stability, and physiological salt stability.

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References

  1. Tiseo K, Huber L, Gilbert M, Robinson TP, Van Boeckel TP. Global trends in antimicrobial use in food animals. Proc Natl Acad Sci USA. 2015;112:5649–54.

    Article  ADS  Google Scholar 

  2. Pei Z, et al. Biological characteristics of a new antibacterial peptide and its antibacterial mechanisms against Gram-negative bacteria. Polish J Vet Sci. 2018;21:533–42.

    CAS  Google Scholar 

  3. Lee W, Lee DG. Fungicidal mechanisms of the antimicrobial peptide Bac8c. Biochim Biophys Acta (BBA) Biomembr. 2015;1848:673–9.

    Article  CAS  Google Scholar 

  4. Wang J, et al. Antimicrobial peptides: promising alternatives in the postfeeding antibiotic era. Med Res Rev. 2019;39:831–59.

    Article  PubMed  CAS  Google Scholar 

  5. Ahmad A, et al. Design of nontoxic analogues of cathelicidin-derived bovine antimicrobial peptide BMAP-27: the role of leucine as well as phenylalanine zipper sequences in determining its toxicity. Biochemistry. 2009;48:10905–17.

    Article  PubMed  CAS  Google Scholar 

  6. Kumar A, et al. Single amino acid substitutions at specific positions of the heptad repeat sequence of piscidin-1 yielded novel analogs that show low cytotoxicity and in vitro and in vivo antiendotoxin activity. Antimicrobial Agents Chemother. 2016;60:3687–99.

    Article  CAS  Google Scholar 

  7. Jia B, et al. High cell selectivity and bactericidal mechanism of symmetric peptides centered on d-Pro–Gly pairs. Int J Mol Sci. 2020;21:1140.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Wang J, et al. Combating drug-resistant fungi with novel imperfectly amphipathic palindromic peptides. J Med Chem. 2018;61:3889–907.

    Article  ADS  PubMed  CAS  Google Scholar 

  9. Shao C, et al. Symmetrical modification of minimized dermaseptins to extend the spectrum of antimicrobials with endotoxin neutralization potency. Int J Mol Sci. 2019;20:1417.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Zhang Y, et al. iTRAQ-based quantitative proteomics analysis reveals inhibitory mechanisms of the antimicrobial peptide MDAP-2 against Salmonella gallinarum. Pol J Vet Sci. 2020;23:405–14.

    Article  PubMed  CAS  Google Scholar 

  11. Huang Y, Huang J, Chen Y. Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell. 2010;1:143–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Chen Y, et al. Rational design of α-helical antimicrobial peptides with enhanced activities and specificity/ therapeutic index. J Biol Chem. 2005;280:12316–29.

    Article  PubMed  CAS  Google Scholar 

  13. Zhu X, et al. Design of imperfectly amphipathic α-helical antimicrobial peptides with enhanced cell selectivity. Acta Biomater. 2014;10:244–57.

    Article  PubMed  CAS  Google Scholar 

  14. Lee J, Lee DG. Antimicrobial peptides (AMPs) with dual mechanisms: membrane disruption and apoptosis. J Microbiol Biotechnol. 2015;25:759–64.

    Article  PubMed  CAS  Google Scholar 

  15. Sass V, et al. Humanbeta-defensin3 inhibits cell wall biosynthesis in Staphylococci. Infect Immun. 2010;78:2793–2800.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Mardirossian M, et al. The host antimicrobial peptide Bac7 (1–35) binds to bacterial ribosomal proteins and inhibits protein synthesis. ChemBiol. 2014;21:1639–47.

    CAS  Google Scholar 

  17. Schmidtchen A, Pasupuleti M, Malmsten M. Effect of hydrophobic modifications in antimicrobial peptides. Adv Colloid Interface Sci. 2014;205:265–74.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This research was funded by the Natural Science Foundation of Jilin Province (Grant number: 20210101040JC), Science and technology project of the 13th five-year plan of Jilin Province Department of Education (Grant number: JJKH20200354KJ).

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Authors and Affiliations

  1. College of Animal Medicine, Jilin Agricultural University, Xincheng Street No. 2888, Changchun, 130118, PR China

    Shuang Yu, Boyan Jia, Ying Zhang, Yue Yu, Zhihua Pei & Hongxia Ma

  2. College of Life Sciences, Jilin Agricultural University, Xincheng Street No. 2888, Changchun, 130118, PR China

    Hongxia Ma

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  1. Shuang Yu
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  2. Boyan Jia
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  3. Ying Zhang
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  4. Yue Yu
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Contributions

ZP and HM conceived and designed the experiments; SY, YZ, and BJ performed the experiments; ZP and BJ analyzed the data; ZP and SY wrote the paper.

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Correspondence to Zhihua Pei or Hongxia Ma.

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Yu, S., Jia, B., Zhang, Y. et al. Design, biological characteristics, and antibacterial mechanism of high therapeutic index antimicrobial peptides with PRRP as central axis. J Antibiot 77, 170–181 (2024). https://doi.org/10.1038/s41429-023-00697-w

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