An Antibacterial Peptide with High Resistance to Trypsin Obtained by Substituting D-Amino Acids for Trypsin Cleavage Sites

Overview

Journal Antibiotics (Basel)

Specialty Pharmacology

Date 2021 Dec 24

PMID 34943677

Citations 9

Authors

Xiaoou Zhao

Mengna Zhang

Inam Muhammad

Qi Cui

Haipeng Zhang

Yu Jia

Qijun Xu

Lingcong Kong

Hongxia Ma

Affiliations

Soon will be listed here.

Abstract

The poor stability of antibacterial peptide to protease limits its clinical application. Among these limitations, trypsin mainly exists in digestive tract, which is an insurmountable obstacle to orally delivered peptides. OM19R is a random curly polyproline cationic antimicrobial peptide, which has high antibacterial activity against some gram-negative bacteria, but its stability against pancreatin is poor. According to the structure-activity relationship of OM19R, all cationic amino acid residues (l-arginine and l-lysine) at the trypsin cleavage sites were replaced with corresponding d-amino acid residues to obtain the designed peptide OM19D, which not only maintained its antibacterial activity but also enhanced the stability of trypsin. Proceeding high concentrations of trypsin and long-time (such as 10 mg/mL, 8 h) treatment, it still had high antibacterial activity (MIC = 16-32 µg/mL). In addition, OM19D also showed high stability to serum, plasma and other environmental factors. It is similar to its parent peptide in secondary structure and mechanism of action. Therefore, this strategy is beneficial to improve the protease stability of antibacterial peptides.

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References

Sato H, Feix J . Peptide-membrane interactions and mechanisms of membrane destruction by amphipathic alpha-helical antimicrobial peptides. Biochim Biophys Acta. 2006; 1758(9):1245-56. DOI: 10.1016/j.bbamem.2006.02.021. View

Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M . Synthetic therapeutic peptides: science and market. Drug Discov Today. 2009; 15(1-2):40-56. DOI: 10.1016/j.drudis.2009.10.009. View

Liu Y, Jia Y, Yang K, Li R, Xiao X, Zhu K . Metformin Restores Tetracyclines Susceptibility against Multidrug Resistant Bacteria. Adv Sci (Weinh). 2020; 7(12):1902227. PMC: 7312304. DOI: 10.1002/advs.201902227. View

Ding X, Yang C, Moreira W, Yuan P, Periaswamy B, de Sessions P . A Macromolecule Reversing Antibiotic Resistance Phenotype and Repurposing Drugs as Potent Antibiotics. Adv Sci (Weinh). 2020; 7(17):2001374. PMC: 7503100. DOI: 10.1002/advs.202001374. View

Pasupuleti M, Schmidtchen A, Malmsten M . Antimicrobial peptides: key components of the innate immune system. Crit Rev Biotechnol. 2011; 32(2):143-71. DOI: 10.3109/07388551.2011.594423. View

Lai Z, Tan P, Zhu Y, Shao C, Shan A, Li L . Highly Stabilized α-Helical Coiled Coils Kill Gram-Negative Bacteria by Multicomplementary Mechanisms under Acidic Condition. ACS Appl Mater Interfaces. 2019; 11(25):22113-22128. DOI: 10.1021/acsami.9b04654. View

Greco I, Hansen J, Jana B, Molchanova N, Oddo A, Thulstrup P . Structure⁻Activity Study, Characterization, and Mechanism of Action of an Antimicrobial Peptoid D2 and Its d- and l-Peptide Analogues. Molecules. 2019; 24(6). PMC: 6470533. DOI: 10.3390/molecules24061121. View

Kim H, Jang J, Kim S, Cho J . De novo generation of short antimicrobial peptides with enhanced stability and cell specificity. J Antimicrob Chemother. 2013; 69(1):121-32. DOI: 10.1093/jac/dkt322. View

Chen Y, Lai Y, Chang C, Tsai Y, Tang C, Jan J . Star-shaped polypeptides exhibit potent antibacterial activities. Nanoscale. 2019; 11(24):11696-11708. DOI: 10.1039/c9nr02012h. View

10.

Hamase K, Morikawa A, Etoh S, Tojo Y, Miyoshi Y, Zaitsu K . Analysis of small amounts of D-amino acids and the study of their physiological functions in mammals. Anal Sci. 2009; 25(8):961-8. DOI: 10.2116/analsci.25.961. View

11.

Stromstedt A, Pasupuleti M, Schmidtchen A, Malmsten M . Evaluation of strategies for improving proteolytic resistance of antimicrobial peptides by using variants of EFK17, an internal segment of LL-37. Antimicrob Agents Chemother. 2008; 53(2):593-602. PMC: 2630634. DOI: 10.1128/AAC.00477-08. View

12.

Jia F, Wang J, Peng J, Zhao P, Kong Z, Wang K . D-amino acid substitution enhances the stability of antimicrobial peptide polybia-CP. Acta Biochim Biophys Sin (Shanghai). 2017; 49(10):916-925. DOI: 10.1093/abbs/gmx091. View

13.

Kang X, Dong F, Shi C, Liu S, Sun J, Chen J . DRAMP 2.0, an updated data repository of antimicrobial peptides. Sci Data. 2019; 6(1):148. PMC: 6692298. DOI: 10.1038/s41597-019-0154-y. View

14.

Rader A, Reichart F, Weinmuller M, Kessler H . Improving oral bioavailability of cyclic peptides by N-methylation. Bioorg Med Chem. 2017; 26(10):2766-2773. DOI: 10.1016/j.bmc.2017.08.031. View

15.

Guo F, Liang Q, Zhang M, Chen W, Chen H, Yun Y . Antibacterial Activity and Mechanism of Linalool against . Molecules. 2021; 26(1). PMC: 7796449. DOI: 10.3390/molecules26010245. View

16.

Wang J, Chou S, Xu L, Zhu X, Dong N, Shan A . High specific selectivity and Membrane-Active Mechanism of the synthetic centrosymmetric α-helical peptides with Gly-Gly pairs. Sci Rep. 2015; 5:15963. PMC: 4632126. DOI: 10.1038/srep15963. View

17.

Qu S, Liu Y, Hu Q, Han Y, Hao Z, Shen J . Programmable antibiotic delivery to combat methicillin-resistant Staphylococcus aureus through precision therapy. J Control Release. 2020; 321:710-717. DOI: 10.1016/j.jconrel.2020.02.048. View

18.

Arias M, Piga K, Hyndman M, Vogel H . Improving the Activity of Trp-Rich Antimicrobial Peptides by Arg/Lys Substitutions and Changing the Length of Cationic Residues. Biomolecules. 2018; 8(2). PMC: 6023086. DOI: 10.3390/biom8020019. View

19.

Miura C, Ohta T, Ozaki Y, Tanaka H, Miura T . Trypsin is a multifunctional factor in spermatogenesis. Proc Natl Acad Sci U S A. 2009; 106(49):20972-7. PMC: 2791598. DOI: 10.1073/pnas.0907631106. View

20.

Dong N, Zhu X, Chou S, Shan A, Li W, Jiang J . Antimicrobial potency and selectivity of simplified symmetric-end peptides. Biomaterials. 2014; 35(27):8028-39. DOI: 10.1016/j.biomaterials.2014.06.005. View