title: Bound to shock: protection from lethal endotoxemic shock by a novel, nontoxic, alkylpolyamine lipopolysaccharide sequestrant.
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 N(1),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.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Lawrence, KS 66047, USA.
authors.forename: Diptesh
authors.initials: D
authors.lastname: Sil
authors.forename: Anurupa
authors.initials: A
authors.lastname: Shrestha
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Kimbrell
authors.forename: Thuan B
authors.initials: TB
authors.lastname: Nguyen
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Adisechan
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Abbo
authors.forename: Subbalakshmi
authors.initials: S
authors.lastname: Malladi
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Miller
authors.forename: Shannon
authors.initials: S
authors.lastname: Short
authors.forename: Jens R
authors.initials: JR
authors.lastname: Cromer
authors.forename: Shravan
authors.initials: S
authors.lastname: Arora
authors.forename: Apurba
authors.initials: A
authors.lastname: Datta
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004731:Endotoxins / Q000737:chemistry* / Q000633:toxicity; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000737:chemistry* / Q000633:toxicity; D008264:Macrophages; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D011112:Polymyxin B / Q000737:chemistry / Q000627:therapeutic use; D012772:Shock, Septic / Q000517:prevention & control*; D013096:Spermine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D013096:Spermine; D011112:Polymyxin B