The proliferation and global expansion of multidrug-resistant (MDR) bacteria have deepened the need to develop novel antimicrobials. Antimicrobial peptides (AMPs) are regarded as promising antibacterial agents because of their broad-spectrum antibacterial activity and multifaceted mechanisms of action with non-specific targets. However, if AMPs are to be applied sustainably, knowledge of how they induce resistance in pathogenic bacteria must be mastered to avoid repeating the traditional antibiotic resistance mistakes currently faced. Furthermore, the evolutionary constraints on the acquisition of AMP resistance by microorganisms in the natural environment, such as functional compatibility and fitness trade-offs, inform the translational application of AMPs. Consequently, the shortcut to achieve sustainable utilization of AMPs is to uncover the evolutionary constraints of bacteria on AMP resistance in nature and find the tricks to exploit these constraints, such as applying AMP cocktails to minimize the efficacy of selection for resistance or combining nanomaterials to maximize the costs of AMP resistance. Altogether, this review dissects the benefits, challenges, and opportunities of utilizing AMPs against disease-causing bacteria, and highlights the use of AMP cocktails or nanomaterials to proactively address potential AMP resistance crises in the future.

多重耐药 (MDR) 细菌的扩散和全球扩张加深了开发新型抗菌药物的需求。抗菌肽 (AMP) 被认为是有前途的抗菌剂，因为它们具有广谱抗菌活性和对非特异性靶标的多方面作用机制。然而，如果要可持续地应用 AMP，就必须掌握它们如何在病原菌中诱导耐药性的知识，以避免重复目前面临的传统抗生素耐药性错误。此外，自然环境中微生物获得 AMP 抗性的进化限制，例如功能相容性和适应性权衡，为 AMP 的转化应用提供了信息。最后，实现 AMP 可持续利用的捷径是揭示细菌在自然界中对 AMP 抗性的进化限制，并找到利用这些限制的技巧，例如应用 AMP 鸡尾酒来最小化抗性选择的功效或结合纳米材料以最大化成本AMP 抗性。总之，这篇综述剖析了利用 AMP 对抗致病细菌的好处、挑战和机遇，并强调了使用 AMP 混合物或纳米材料来主动解决未来潜在的 AMP 耐药性危机。