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    Bound To Shock: Protection from Lethal Endotoxemic Shock by a Novel, Nontoxic, Alkylpolyamine Lipopolysaccharide Sequestrant

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    DavidS_AAC_51(8)2811.pdf (717.4Kb)
    Issue Date
    2007-08
    Author
    Sil, Diptesh
    Shrestha, Anurupa
    Kimbrell, Matthew R.
    Nguyen, Thuan B.
    Adisechan, Ashok K.
    Balakrishna, Rajalakshmi
    Abbo, Benjamin G.
    Malladi, Subbalakshmi S.
    Miller, Kelly A.
    Short, Shannon
    Cromer, Jens R.
    Arora, Shravan
    Datta, Apurba
    David, Sunil A.
    Publisher
    The American Society for Microbiology
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
    Metadata
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    Abstract
    Lipopolysaccharide (LPS), or endotoxin, a structural component of gram-negative bacterial outer membranes, plays a key role in the pathogenesis of septic shock, a syndrome of severe systemic inflammation which leads to multiple-system organ failure. Despite advances in antimicrobial chemotherapy, sepsis continues to be the commonest cause of death in the critically ill patient. This is attributable to the lack of therapeutic options that aim at limiting the exposure to the toxin and the prevention of subsequent downstream inflammatory processes. Polymyxin B (PMB), a peptide antibiotic, is a prototype small molecule that binds and neutralizes LPS toxicity. However, the antibiotic is too toxic for systemic use as an LPS sequestrant. Based on a nuclear magnetic resonance-derived model of polymyxin B-LPS complex, we had earlier identified the pharmacophore necessary for optimal recognition and neutralization of the toxin. Iterative cycles of pharmacophore-based ligand design and evaluation have yielded a synthetically easily accessible N1,mono-alkyl-mono-homologated spermine derivative, DS-96. We have found that DS-96 binds LPS and neutralizes its toxicity with a potency indistinguishable from that of PMB in a wide range of in vitro assays, affords complete protection in a murine model of LPS-induced lethality, and is apparently nontoxic in vertebrate animal models.
    URI
    http://hdl.handle.net/1808/17653
    DOI
    https://doi.org/10.1128/AAC.00200-07
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    • Medicinal Chemistry Scholarly Works [242]
    Citation
    Sil et. al. "Bound To Shock: Protection from Lethal Endotoxemic Shock by a Novel, Nontoxic, Alkylpolyamine Lipopolysaccharide Sequestrant." Antimicrob. Agents Chemother. August 2007 vol. 51 no. 8 2811-2819. http://dx.doi.org/10.1128/AAC.00200-07

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    KU Libraries
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    785-864-8983

    KU Libraries
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    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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