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Antimicrobial Agents and Chemotherapy, June 2005, p. 2307-2313, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2307-2313.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Combination of Antimicrobial and Endotoxin-Neutralizing Activities of Novel Oleoylamines

Mateja Zorko,1,{dagger} Andreja Majerle,1,{dagger} David Sarlah,2 Mateja Mancek Keber,1 Barbara Mohar,2 and Roman Jerala1*

National Institute of Chemistry, Laboratory of Biotechnology,1 Laboratory of Organic and Medicinal Chemistry, Ljubljana, Slovenia2

Received 20 July 2004/ Returned for modification 19 August 2004/ Accepted 4 February 2005

A combination of antimicrobial and endotoxin-neutralizing activities is desired in order to prevent progression from infection to sepsis due to the release of lipopolysaccharide from dying gram-negative bacteria. Lipopolyamines have emerged as a new type of endotoxin-neutralizing compound, but their antimicrobial activity has not been investigated. We synthesized a series of 10 oleoylamines differing in the polyamino head group, particularly in the number and separation between nitrogen atoms and the position of the oleoyl moiety. Compounds showed activity against both gram-negative and gram-positive bacteria in the micromolar range. Compounds were able to provide penetration of ethidium bromide into bacteria, indicating effects on the bacterial membrane. Oleoylamines neutralized endotoxin in Limulus amoebocyte lysate assays and by neutralization of tumor necrosis factor alpha release in human blood. Comparison of biological activities of compounds identified structural properties responsible for antimicrobial activity, and quantitative structure-property relationship analysis provided a quantitative model for prediction of activity of oleoylamines.

* Corresponding author. Mailing address: Laboratory of Biotechnology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia. Phone: 386-1-4760335. Fax: 386-1-4760300. E-mail: roman.jerala{at}ki.si.

{dagger} M.Z. and A.M. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, June 2005, p. 2307-2313, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2307-2313.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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