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Antimicrobial Agents and Chemotherapy, January 2009, p. 57-62, Vol. 53, No. 1
0066-4804/09/$08.00+0 doi:10.1128/AAC.00812-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Structure-Activity Relationships of Antimicrobial and Lipoteichoic Acid-Sequestering Properties in Polyamine Sulfonamides 
Hemamali J. Warshakoon,1
Mark R. Burns,2* and
Sunil A. David1*
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045,1 MediQuest Therapeutics, Inc., 22322 20th Ave. SE, Bothell, Washington 980212
Received 19 June 2008/ Returned for modification 6 October 2008/ Accepted 17 October 2008
We have recently confirmed that lipoteichoic acid (LTA), a major constituent of the gram-positive bacterial surface, is the endotoxin of gram-positive bacteria that induces proinflammatory molecules in a Toll-like receptor 2 (TLR2)-dependent manner. LTA is an anionic amphipath whose physicochemical properties are similar to those of lipopolysaccharide (LPS), which is found on the outer leaflet of the outer membranes of gram-negative organisms. Hypothesizing that compounds that sequester LPS could also bind to and inhibit LTA-induced cellular activation, we screened congeneric series of polyamine sulfonamides which we had previously shown effectively neutralized LPS both in vitro and in animal models of endotoxemia. We observed that these compounds do bind to and neutralize LTA, as reflected by the inhibition of TLR2-mediated NF-
B induction in reporter gene assays. Structure-activity studies showed a clear dependence of the acyl chain length on activity against LTA in compounds with spermine and homospermine scaffolds. We then sought to examine possible correlations between the neutralizing potency toward LTA and antimicrobial activity in Staphylococcus aureus. A linear relationship between LTA sequestration activity and antimicrobial activity for compounds with a spermine backbone was observed, while all compounds with a homospermine backbone were equally active against S. aureus, regardless of their neutralizing potency toward LTA. These results suggest that the number of protonatable charges is a key determinant of the activity toward the membranes of gram-positive bacteria. The development of resistance to membrane-active antibiotics has been relatively slower than that to conventional antibiotics, and it is possible that compounds such as the acylpolyamines may be useful clinically, provided that they have an acceptable safety profile and margin of safety. A more detailed understanding of the mechanisms of interactions of these compounds with LPS and LTA, as well as the gram-negative and -positive bacterial cell surfaces, will be instructive and should allow the rational design of analogues which combine antisepsis and antibacterial properties.
* Corresponding author. Mailing address for Sunil A. David: Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047. Phone: (785) 864-1610. Fax: (785) 864-1920. E-mail: sdavid{at}ku.edu. Mailing address for Mark R. Burns: MediQuest Therapeutics, Inc., 22322 20th Ave. SE, Bothell, WA 98021. Phone: (425) 398-9580, ext 15. Fax: (425) 398-9590. E-mail: markburns{at}mqti.com
Published ahead of print on 27 October 2008.
Antimicrobial Agents and Chemotherapy, January 2009, p. 57-62, Vol. 53, No. 1
0066-4804/09/$08.00+0 doi:10.1128/AAC.00812-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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