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Design of a potent antibiotic peptide based on the active region of human defensin 5.

Wang C, Shen M, Gohain N, Tolbert WD, Chen F, Zhang N, Yang K, Wang A, Su Y, Cheng T, Zhao J, Pazgier M, Wang J
J Med Chem 58 3083-93 (2015)
Cited: 27 times
EuropePMC logo PMID: 25782105

Abstract

Human defensin 5 (HD5) is a broad-spectrum antibacterial peptide with a C-terminal active region. To promote the development of this peptide into an antibiotic, we initially substituted Glu21 with Arg because it is an electronegative residue located around the active region. Although detrimental to dimer formation, the E21R substitution markedly enhanced the antibacterial activity of HD5 and increased its ability to penetrate cell membranes, demonstrating that increasing the electropositive charge compensated for the effect of dimer disruption. Subsequently, a partial Arg scanning mutagenesis was performed, and Thr7 was selected for replacement with Arg to further strengthen the antibacterial activity. The newly designed peptide, T7E21R-HD5, exhibited potent antibacterial activity, even in saline and serum solutions. In contrast to monomeric E21R-HD5, T7E21R-HD5 assembled into an atypical dimer with parallel β strands, thus expanding the role of increasing electropositive charge in bactericidal activity and providing a useful guide for further defensin-derived antibiotic design.

Reviews citing this publication (9)

  1. Considerations and Caveats in Combating ESKAPE Pathogens against Nosocomial Infections. Ma YX, Wang CY, Li YY, Li J, Wan QQ, Chen JH, Tay FR, Niu LN. Adv Sci (Weinh) 7 1901872 (2020)
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Articles citing this publication (18)

  1. Human Intestinal Defensin 5 Inhibits SARS-CoV-2 Invasion by Cloaking ACE2. Wang C, Wang S, Li D, Wei DQ, Zhao J, Wang J. Gastroenterology 159 1145-1147.e4 (2020)
  2. Reduction Impairs the Antibacterial Activity but Benefits the LPS Neutralization Ability of Human Enteric Defensin 5. Wang C, Shen M, Zhang N, Wang S, Xu Y, Chen S, Chen F, Yang K, He T, Wang A, Su Y, Cheng T, Zhao J, Wang J. Sci Rep 6 22875 (2016)
  3. Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease. Williams AD, Korolkova OY, Sakwe AM, Geiger TM, James SD, Muldoon RL, Herline AJ, Goodwin JS, Izban MG, Washington MK, Smoot DT, Ballard BR, Gazouli M, M'Koma AE. PLoS One 12 e0179710 (2017)
  4. Succinylated casein-coated peptide-mesoporous silica nanoparticles as an antibiotic against intestinal bacterial infection. Zhao G, Chen Y, He Y, Chen F, Gong Y, Chen S, Xu Y, Su Y, Wang C, Wang J. Biomater Sci 7 2440-2451 (2019)
  5. Variations in the interaction of human defensins with Escherichia coli: Possible implications in bacterial killing. Mathew B, Nagaraj R. PLoS One 12 e0175858 (2017)
  6. A Simplified Derivative of Human Defensin 5 with Potent and Efficient Activity against Multidrug-Resistant Acinetobacter baumannii. Wang C, Zhao G, Wang S, Chen Y, Gong Y, Chen S, Xu Y, Hu M, Wang X, Zeng H, Wang A, Liu D, Su Y, Cheng T, Chen F, Wang J. Antimicrob Agents Chemother 62 e01504-17 (2018)
  7. α-Defensin HD5 Stabilizes Human Papillomavirus 16 Capsid/Core Interactions. Gulati NM, Miyagi M, Wiens ME, Smith JG, Stewart PL. Pathog Immun 4 196-234 (2019)
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  9. Cell-Selective Pore Forming Antimicrobial Peptides of the Prodomain of Human Furin: A Conserved Aromatic/Cationic Sequence Mapping, Membrane Disruption, and Atomic-Resolution Structure and Dynamics. Sinha S, Harioudh MK, Dewangan RP, Ng WJ, Ghosh JK, Bhattacharjya S. ACS Omega 3 14650-14664 (2018)
  10. Nanodefensin-encased hydrogel with dual bactericidal and pro-regenerative functions for advanced wound therapy. Luo G, Sun Y, Zhang J, Xu Z, Lu W, Wang H, Zhang Y, Li H, Mao Z, Ye S, Cheng B, Fang X. Theranostics 11 3642-3660 (2021)
  11. Antagonism of Adherent Invasive E. coli LF82 With Human α-defensin 5 in the Follicle-associated Epithelium of Patients With Ileal Crohn's Disease. Alkaissi LY, Winberg ME, Heil SDS, Haapaniemi S, Myrelid P, Stange EF, Söderholm JD, Keita ÅV. Inflamm Bowel Dis 27 1116-1127 (2021)
  12. Simplified Head-to-Tail Cyclic Polypeptides as Biomaterial-Associated Antimicrobials with Endotoxin Neutralizing and Anti-Inflammatory Capabilities. Dong N, Wang C, Li X, Guo Y, Li X. Int J Mol Sci 20 E5904 (2019)
  13. Antimicrobial peptide ROAD-1 triggers phase change in local membrane environment to execute its activity. Vasudevan SV, Kumar A. J Mol Model 25 281 (2019)
  14. Dimeric lipo-α/sulfono-γ-AA hybrid peptides as broad-spectrum antibiotic agents. Wei L, Gao R, Wang M, Wang Y, Shi Y, Gu M, Cai J. Biomater Sci 9 3410-3424 (2021)
  15. Expression of the Shrimp wap gene in Drosophila elicits defense responses and protease inhibitory activity. Li D, Luan Y, Wang L, Qi M, Wang J, Xu J, Arefin B, Li M. Sci Rep 8 8779 (2018)
  16. Screening and characterization of the scFv for chimeric antigen receptor T cells targeting CEA-positive carcinoma. Zhang C, Wang L, Zhang Q, Shen J, Huang X, Wang M, Huang Y, Chen J, Xu Y, Zhao W, Qi Y, Li Y, Ou Y, Yang Z, Qian C. Front Immunol 14 1182409 (2023)
  17. Ubiquitous Colonic Ileal Metaplasia Consistent with the Diagnosis of Crohn's Colitis among Indeterminate Colitis Cohorts. Breaux WA, Bragg MA, M'Koma AE. Med Res Arch 11 4188 (2023)
  18. γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5. Zhao G, Jia C, Zhu C, Fang M, Li C, Chen Y, He Y, Han S, He Y, Gao J, Wang T, Wang C, Wang J. Membranes (Basel) 13 51 (2022)


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