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Antibacterial, Antibiofilm, and Anti-inflammatory Effects of a Novel Thrombin-Derived Peptide in Sepsis Models: Insights into Underlying Mechanisms

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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Med. Chem. 2024, 67, 21, 19791-19812
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    Antibacterial, Antibiofilm, and Anti-inflammatory Effects of a Novel Thrombin-Derived Peptide in Sepsis Models: Insights into Underlying Mechanisms
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    • S. Dinesh Kumar
      S. Dinesh Kumar
      Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea
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    • Jin Kyeong Lee
      Jin Kyeong Lee
      Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea
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      Orcidhttps://orcid.org/0009-0000-9133-8688
    • Naveen Kumar Radhakrishnan
      Naveen Kumar Radhakrishnan
      Graduate School of Biomedical Science, Chosun University, Gwangju 61452, Republic of Korea
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    • Jeong Kyu Bang
      Jeong Kyu Bang
      Division of Magnetic Resonance, Korea Basic Science Institute (KBSI), Ochang, Chung Buk 28119, Republic of Korea
      Dandicure Inc, Ochang, Chung Buk 28119, Republic of Korea
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      Orcidhttps://orcid.org/0000-0001-5916-0912
    • Byeongkwon Kim
      Byeongkwon Kim
      Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea
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    • Shubhash Chandra Chaudhary
      Shubhash Chandra Chaudhary
      Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea
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    • Ajish Chelladurai
      Ajish Chelladurai
      Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea
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    • Byambasuren Ganbaatar
      Byambasuren Ganbaatar
      Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
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    • Eun Young Kim
      Eun Young Kim
      Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea
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    • Chul Won Lee
      Chul Won Lee
      Department of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
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    • Sungtae Yang
      Sungtae Yang
      Department of Microbiology, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea
      Institute of Well-Aging Medicare & CSU G-LAMP Project Group, Chosun University, Gwangju 61452, Republic of Korea
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      Orcidhttps://orcid.org/0000-0002-5648-5938
    • Yangmee Kim*
      Yangmee Kim
      Department of Bioscience and Biotechnology, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of Korea
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0001-6438-4718
    • Song Yub Shin*
      Song Yub Shin
      Department of Cellular & Molecular Medicine, School of Medicine, Chosun University, Gwangju 61452, Republic of Korea
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-3030-7973
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 21, 19791–19812
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    https://doi.org/10.1021/acs.jmedchem.4c02157
    Published October 30, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    We developed two short helical antimicrobial peptides, HVF18-a3 and its d-enantiomer, HVF18-a3-d, derived from the thrombin C-terminal peptide HVF18. These peptides exhibit potent antimicrobial activity against various bacteria by compromising both the outer and inner membranes, with low hemolytic activity. They are stable in the presence of physiological salts and human serum, exhibiting a low potential for developing drug resistance and excellent antibiofilm activity against Gram-negative bacteria. HVF18-a3-d also neutralized lipopolysaccharide (LPS) through direct binding interactions and suppressed the production of inflammatory cytokines through the inflammatory signaling pathway mediated by Toll-like receptor 4 in RAW264.7 cells stimulated with LPS. Both pre- and post-treatment with HVF18-a3-d significantly protected mice against fatal septic shock induced by carbapenem resistant Acinetobacter baumannii. These findings suggest HVF18-a3 and HVF18-a3-d are promising candidates for developing antibiotics against Gram-negative sepsis.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c02157.

    • Materials, and bacterial strains; analytical RP-HPLC profiles and retention time (min) of synthetic HVF18 and its analogs (Figure S1). ESI-MS of HVF18 and HVF18-a1 (Figure S2); ESI-MS of HVF18-a2 and HVF18-a3 (Figure S3); ESI-MS of HVF18-a4 and HVF18-a3-d (Figure S4); dose-dependent lysis of HVF18 and its analogs and melittin against sheep red blood cells (sRBCs) (Figure S5); CD spectra of HVF18 and its analogs in aqueous buffer, 50% TFE and 30 mM SDS and 0.1% LPS (Figure S6); peptide-induced membrane depolarization measured with DiSC3(5) against E. coli ML-35 (Figure S7); in vitro biofilm formation inhibition and eradication of preformed biofilm of HVF18-a3 and HVF18-a3-d against CRAB (CCARM 12005) (Figure S8); binding affinity of HVF18-a3 and LL-37 to cell-free LPS and LPS from E. coli (KCTC 1682) for the dose-dependent displacement of BODIPY-TR-cadaverine (Figure S9); effect of peptides on fibrin clot formation (Figure S10); mean residual ellipticity at 222 nm ([θ]222) and percent α-helical contents of HVF18 and its analogs in aqueous buffer, 50% TFE, 30 mM SDS and 0.1% LPS (Table S1); antibacterial activities of HVF18-a3-d, melittin, polymyxin B and imipenem against A. baumannii and CRAB strains (Table S2) (PDF)

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2024, 67, 21, 19791–19812
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jmedchem.4c02157
    Published October 30, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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