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.

Figure 1.

Evolved resistance to pexiganan has associated costs that can be ameliorated by compensatory adaptation. (a) V_MAX plotted against pexiganan MIC for ancestral and evolved bacteria. Asterisks indicate significant difference by t-test between ancestral and evolved V_MAX (**p ≤ 0.001, *** p ≤ 0.0001). (b) V_MAX of ancestral and evolved SA3 bacteria before (light grey) and after (dark grey) selection in the absence of pexiganan. All compensated bacteria retained resistance to pexiganan (data not shown).

Figure 2.

Resistance to pexiganan provides cross-resistance to HNP-1. Bars represent the ratio of growth rates in presence versus absence of HNP-1 for ancestral (light grey) and evolved (dark grey) bacteria; a value of 1 represents no inhibition of growth by HNP-1.