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Antimicrobial Agents and Chemotherapy, March 2006, p. 852-861, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.852-861.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines

Rajalakshmi Balakrishna,1 Stewart J. Wood,1 Thuan B. Nguyen,1 Kelly A. Miller,1 E. V. K. Suresh Kumar,1 Apurba Datta,2 and Sunil A. David1*

Department of Medicinal Chemistry, University of Kansas, Life Sciences Research Laboratories, 1501 Wakarusa Drive, Lawrence, Kansas 66049,1 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 660452

Received 6 June 2005/ Returned for modification 18 October 2005/ Accepted 11 December 2005

A homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8 or C9 chains, was found to profoundly sensitize Escherichia coli to hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.

* Corresponding author. Mailing address: 145E Bldg. B, University of Kansas Life Sciences Research Laboratories, 1501 Wakarusa Drive, Lawrence, KS 66049. Phone: (785) 330-4316. Fax: (785) 330-4332. E-mail: sdavid{at}ku.edu.

Antimicrobial Agents and Chemotherapy, March 2006, p. 852-861, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.852-861.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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