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Antimicrob. Agents Chemother. doi:10.1128/AAC.00854-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The PhoQ Activating Potential of Antimicrobial Peptides Contributes to Antimicrobial Efficacy and Predicts Induction of Bacterial Resistance

Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E3, Canada; Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada; Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada

^* To whom correspondence should be addressed. Email: scott.napper{at}usask.ca.

	Abstract

Antimicrobial peptides (AMPs) are among the leading candidates to replace antibiotics which have been rendered ineffective by the evolution of resistant bacterial strains. Concerns do exist, however, that therapeutic administration of AMPs may also select for resistant strains but with much more dire consequences as these peptides represent an endogenous and essential component of host immune defense. The recent demonstration that AMPs function as ligands for the bacterial sensory kinase PhoQ to the initiation of virulence and adaptive responses lends credence to these concerns. While the ability to serve as PhoQ ligands suggests that therapeutic administration of AMPs could: a) exasperate infections by promoting bacterial virulence and b) select resistant mutants by encouraging adaptive behaviors, it also provides a rationale basis for AMP selection and optimization. Here we demonstrate that derivatives of a representative AMP have differential abilities to serve as PhoQ ligands and that this correlates with the ability to induce bacterial adaptive responses. We propose that PhoQ activating potential is a logical parameter for optimization and introduce a novel strategy for treatment of minimal bacteriocidal concentration data that permits discrimination and quantification of the contributions of PhoQ activating potential and direct antimicrobial activity to net antimicrobial efficiency.