Therapeutic antimicrobial peptides may compromise natural immunity
Michelle G. J. L. Habets and Michael A. Brockhurst*
Author Affiliations
Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
*Author for correspondence (brock@liv.ac.uk).
Abstract
Antimicrobial peptides (AMPs) have been proposed as a promising new class of antimicrobials despite warnings that therapeutic use could drive the evolution of pathogens resistant to our own immunity peptides. Using experimental evolution, we demonstrate that Staphylococcus aureus rapidly evolved resistance to pexiganan, a drug-candidate for diabetic leg ulcer infections. Evolved resistance was costly in terms of impaired growth rate, but costs-of-resistance were completely ameliorated by compensatory adaptation. Crucially, we show that, in some populations, experimentally evolved resistance to pexiganan provided S. aureus with cross-resistance to human-neutrophil-defensin-1, a key component of the innate immune response to infection. This unintended consequence of therapeutic use could drastically undermine our innate immune system's ability to control and clear microbial infections. Our results therefore highlight grave potential risks of AMP therapies, with implications for their development.
antibiotic resistance, antimicrobial peptide, compensatory adaptation, cost-of-resistance, experimental evolution, innate immunity
Received December 8, 2011.
Accepted January 5, 2012.
This journal is © 2012 The Royal Society
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