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Antimicrobial Agents and Chemotherapy, August 2007, p. 2811-2819, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00200-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Diptesh Sil, Anurupa Shrestha, Matthew R. Kimbrell, Thuan B. Nguyen, Ashok K. Adisechan, Rajalakshmi Balakrishna, Benjamin G. Abbo, Subbalakshmi Malladi, Kelly A. Miller, Shannon Short, Jens R. Cromer, Shravan Arora, Apurba Datta, and Sunil A. David*

Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas

Received 11 February 2007/ Returned for modification 23 April 2007/ Accepted 28 May 2007

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.

* Corresponding author. Mailing address: Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence, KS 66047. Phone: (785) 864-1610. Fax: (785) 864-1961. E-mail: sdavid{at}ku.edu

{triangledown} Published ahead of print on 4 June 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2811-2819, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.00200-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Warshakoon, H. J., Burns, M. R., David, S. A. (2009). Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides. Antimicrob. Agents Chemother. 53: 57-62 [Abstract] [Full Text]  


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