Therapeutic antimicrobial peptides may compromise natural immunity.

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.

• Authors: Michelle G J L Habets, Michael A Brockhurst
• Journal: Biology letters (Biol Lett) Vol. 8 Issue 3 Pg. 416-8 (Jun 23 2012) ISSN: 1744-957X [Electronic] England
• PMID: 22279153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Antimicrobial Cationic Peptides
• alpha-Defensins
• human neutrophil peptide 1
• pexiganan

Topics

• Anti-Infective Agents (pharmacology)
• Antimicrobial Cationic Peptides (pharmacology)
• Biological Evolution
• Drug Resistance, Bacterial
• Drug Resistance, Multiple
• Humans
• Immunity, Innate
• Selection, Genetic
• Staphylococcal Infections (immunology, microbiology)
• Staphylococcus aureus (drug effects, genetics)
• alpha-Defensins (pharmacology)