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Antimicrobial Agents and Chemotherapy, April 2006, p. 1480-1488, Vol. 50, No. 4
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.4.1480-1488.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Adding Selectivity to Antimicrobial Peptides: Rational Design of a Multidomain Peptide against Pseudomonas spp.

Department of Microbiology, Immunology, and Molecular Genetics,¹ School of Dentistry, University of California, Los Angeles, California 90095,² C3 Jian, Inc., Sequim, Washington 98382³

Received 12 September 2005/ Returned for modification 2 November 2005/ Accepted 13 January 2006

Currently available antimicrobials exhibit broad killing with regard to bacterial genera and species. Indiscriminate killing of microbes by these conventional antibiotics can disrupt the ecological balance of the indigenous microbial flora, often resulting in negative clinical consequences. Species-specific antimicrobials capable of precisely targeting pathogenic bacteria without damaging benign microorganisms provide a means of avoiding this problem. In this communication, we report the successful creation of the first synthetic, target-specific antimicrobial peptide, G10KHc, via addition of a rationally designed Pseudomonas-specific targeting moiety (KH) to a generally killing peptide (novispirin G10). The resulting chimeric peptide showed enhanced bactericidal activity and faster killing kinetics against Pseudomonas spp. than G10 alone. The enhanced killing activities are due to increased binding and penetration of the outer membrane of Pseudomonas sp. cells. These properties were not observed in tests of untargeted bacterial species, and this specificity allowed G10KHc to selectively eliminate Pseudomonas spp. from mixed cultures. This work lays a foundation for generating target-specific "smart" antimicrobials to complement currently available conventional antibiotics.

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