Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
Biol Lett. 2012 Jun 23;8(3):416-8. doi: 10.1098/rsbl.2011.1203. Epub 2012 Jan 25.
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.
抗菌肽 (AMPs) 被认为是一类很有前途的新型抗菌药物，尽管有警告称，治疗性使用可能会导致病原体对我们自身免疫肽产生耐药性。通过实验进化，我们证明金黄色葡萄球菌对治疗糖尿病足溃疡感染的候选药物pexiganan迅速产生了耐药性。从生长速度受损的角度来看，进化产生的耐药性是有代价的，但通过补偿性适应，耐药性的代价完全得到了缓解。至关重要的是，我们表明，在某些群体中，pexiganan 的实验进化抗性赋予了金黄色葡萄球菌对人中性粒细胞防御素-1 的交叉耐药性，人中性粒细胞防御素-1 是感染后先天免疫系统对抗微生物感染的关键组成部分。这种治疗性使用的意外后果可能会极大地削弱我们先天免疫系统控制和清除微生物感染的能力。因此，我们的研究结果突出了 AMP 治疗的严重潜在风险，这对它们的发展具有重要意义。
