Antimicrobial peptides: Application informed by evolution.
Antimicrobial peptides: Application informed by evolution.
复制标题
DOI：
10.1126/science.aau5480
复制
发表时间：
2020-05-01
期刊：
影响因子：
--
通讯作者：
Rolff J
中科院分区：
文献类型：
--
作者：
Lazzaro BP;Zasloff M;Rolff J
抗菌肽（AMPs）是一种具有有效抗菌、抗病毒和抗真菌活性的小蛋白质。AMP在多细胞真核生物中普遍存在，大多数植物和动物物种在上皮组织中表达数十种不同的AMP基因并对感染作出反应。amp的多样性和效力使它们成为转化应用的有吸引力的候选者，其中一些已经在临床试验中。然而，如果要有效和可持续地使用抗菌药物，就必须了解它们的自然生物学和进化，以减少附带伤害的风险，避免目前传统抗生素面临的耐药性危机。在过去25年的大部分时间里，流行的观点一直认为抗菌肽通常是非特异性的，功能上是冗余的——只要它们的产生速度足够快，能够达到控制感染的阈值，它们在很大程度上是可以互换的。支持这一模型的分子进化观察表明，AMP基因在物种内部和物种之间迅速复制和假原化，通常在初级氨基酸序列水平上几乎没有进化。此外，人们认为amp的生物化学简单性从根本上反映了不可抗拒的作用方式，包括通过形成开放孔来渗透细胞包膜，这被认为在很大程度上阻止了细菌的耐药性进化。然而，过去5年的新证据已经开始推翻这一模式。我们现在知道AMP可以表现出显著的特异性水平，并且AMP基因家族的一些进化降解可能是适应性的。我们正在了解到amp的遗传变异，即使是在单个氨基酸的水平上，也能极大地改变对感染的抵抗力。目前已有多种物种间相同氨基酸变异趋同进化和物种间共有等位基因多样性趋同进化的文献。越来越清楚的是，amp具有高度多样化的功能，它们在各种生物过程中发挥作用，包括对共生群落的调节。细菌可以进化出对抗菌肽的耐药性，这一点也越来越明显，尽管抗菌肽的药效学和杀伤机制比传统抗生素更有利于防止耐药性进化。amp在转化应用方面具有相当大的前景，但开发其潜力将需要更复杂的基础理解。amp在体内具有协同作用，新出现的证据表明，它们在生物学背景下的活性可能无法通过经典的体外分析完全捕获。需要进一步发展数学方法来研究协同作用，特别是高阶相互作用，以便合理地开发低浓度的高效鸡尾酒。应利用抗菌肽与常规抗生素之间的协同作用来挽救目前因耐药而丧失的药物。应该从生命的所有领域中挖掘amp：尽管已经从代表地球上生命广度的分类群中描述了超过3100种自然产生的amp，但在临床试验中，近40%的amp来自人类。这是有潜在风险的，因为对这些amp的任何进化抗性都可能导致对内源性人体免疫的附带抗性。抗菌肽的生化特性和药效学特性使其比传统抗生素更不易发生耐药性进化，但仍应谨慎使用。通过了解特定amp在自然环境中的作用以及它们的进化史如何预测它们未来的效用，将大大提高amp在临床和其他应用环境中的转化应用。如果我们结合amp进化多样化的见解，它们在协同鸡尾酒的背景下的活动，以及我们对如何限制耐药性进化的日益增长的理解，我们可能会避免重复导致当前抗生素耐药性危机的错误。抗菌肽（Antimicrobial peptides, AMPs）是多细胞生物免疫防御的重要组成部分，是目前正在开发的抗感染药物。传统上认为amp具有广谱活性和简单的动力学，但最近的证据表明其具有意想不到的特异性和高协同能力。对AMP基因的分子进化和群体遗传学的深入研究揭示了AMP基因多态性的适应性维持以及AMP活性的适应性丧失的更多证据。抗菌肽的药效学特性可以减少目标微生物的耐药性进化，而且抗菌肽可以相互协同作用，也可以与传统抗生素协同作用。这两种特性使amp对翻译应用具有吸引力。然而，如果抗菌肽要在临床上使用，了解其自然生物学是至关重要的，以减少附带伤害的风险，避免传统抗生素目前面临的耐药性危机。从整个生命之树和amp的适应性进化中研究amp的综合见解将为它们在自然环境中的应用和理解amp提供信息。在自然界中，amp是高度多样化的，大多数amp（超过1000种）在两栖类中被描述。它们在体内以协同鸡尾酒的形式释放。体外研究发现，增效作用频繁，与常规抗生素相比，抗菌肽的其他特性导致耐药性进化的可能性较低。
Antimicrobial peptides (AMPs) are small proteins with potent antibacterial, antiviral, and antifungal activity. AMPs are ubiquitous among multicellular eukaryotes, with most plant and animal species expressing dozens of distinct AMP genes in epithelial tissues and in response to infection. The diversity and potency of AMPs make them attractive candidates for translational application, and several are already in clinical trials. However, if AMPs are to be used effectively and sustainably, it will be imperative to understand their natural biology and evolution in order to lessen the risk of collateral harm and avoid the resistance crisis currently facing conventional antibiotics. For most of the past 25 years, the prevailing wisdom has been that AMPs are generally nonspecific and functionally redundant—largely interchangeable provided that they were produced quickly enough to a threshold that could contain infection. Support for this model was drawn from molecular evolutionary observations that AMP genes are rapidly duplicated and pseudogenized within and between species, often with little evolution at the level of the primary amino acid sequence. Furthermore, it was believed that the biochemical simplicity of AMPs reflected fundamentally irresistible modes of action, including permeabilization of the cell envelope through the formation of open pores, which was assumed to largely prevent bacterial evolution of resistance. New evidence within the past 5 years, however, has begun to overturn that model. We now know that AMPs can exhibit remarkable levels of specificity and that some of the evolutionary degradation of AMP gene families may be adaptive. We are learning that genetic variability in AMPs, even at the level of single amino acids, can dramatically alter resistance to infection. There are now multiple documentations of convergent evolution of identical amino acid variants between species and of shared allelic diversity between species. It is increasingly clear that AMPs are highly functionally diversified and that they play roles in varied biological processes, including the regulation of symbiotic communities. It is also becoming apparent that bacteria can evolve resistance to AMPs, although the pharmacodynamics and mechanisms of killing of AMPs are much more favorable than those of conventional antibiotics for the prevention of resistance evolution. AMPs hold considerable promise for translational applications, but developing their potential will require more sophisticated foundational understanding. AMPs function synergistically in vivo, and emerging evidence indicates that their activities in biological contexts may not be fully captured with classical in vitro assays. Further development of mathematical approaches to study synergies will be required, especially for higher-order interactions, in order to rationally develop cocktails that have high efficacy at low concentrations. Synergies between AMPs and conventional antibiotics should be exploited to rescue drugs that are currently lost to resistance. AMPs should be mined from all domains of life: Although more than 3100 naturally occurring AMPs have been described from taxa representing the breadth of life on earth, almost 40% of AMPs under clinical trial are of human origin. This is potentially risky because any evolved resistance to those AMPs may result in collateral resistance to endogenous human immunity. The biochemical properties and pharmacodynamics of AMPs make them far more refractory to resistance evolution than conventional antibiotics, but care should still be taken to deploy them responsibly. Translational use of AMPs in clinical and other applied settings will be greatly enhanced by understanding how specific AMPs function in their natural contexts and how their evolutionary history may predict their future utility. If we combine the insights from the evolutionary diversification of the AMPs, their activity in the context of synergistic cocktails, and our growing understanding of how to limit resistance evolution, we may avoid repeating the mistakes that have resulted in the current crisis of antibiotic resistance. Antimicrobial peptides (AMPs) are essential components of immune defenses of multicellular organisms and are currently in development as anti-infective drugs. AMPs have been classically assumed to have broad-spectrum activity and simple kinetics, but recent evidence suggests an unexpected degree of specificity and a high capacity for synergies. Deeper evaluation of the molecular evolution and population genetics of AMP genes reveals more evidence for adaptive maintenance of polymorphism in AMP genes than has previously been appreciated, as well as adaptive loss of AMP activity. AMPs exhibit pharmacodynamic properties that reduce the evolution of resistance in target microbes, and AMPs may synergize with one another and with conventional antibiotics. Both of these properties make AMPs attractive for translational applications. However, if AMPs are to be used clinically, it is crucial to understand their natural biology in order to lessen the risk of collateral harm and avoid the crisis of resistance now facing conventional antibiotics. The combined insight from studying AMPs across the tree of life and the adaptive evolution of AMPs will inform their application and the understanding of AMPs in their natural context. In nature, AMPs are highly diverse, with most AMPs (more than 1000) described in Amphibia. They are released as synergistic cocktails in vivo. In vitro studies found that synergies are frequent and that other traits of AMPs result in a low probability of resistance evolution compared with conventional antibiotics.
登录
查看更多内容
影响因子：
6.4
作者：
Chen F;Krasity BC;Peyer SM;Koehler S;Ruby EG;Zhang X;McFall-Ngai MJ
通讯作者：
McFall-Ngai MJ
比较抗菌肽和常见抗生素之间对金黄色葡萄球菌的选择。
影响因子：
3.7
作者：
Dobson AJ;Purves J;Kamysz W;Rolff J
通讯作者：
Rolff J
影响因子：
3.8
作者：
El Shazely, Baydaa;Urabanski, Arkadiusz;Rolff, Jens
通讯作者：
Rolff, Jens
DOI：
10.1126/science.1220761
发表时间：
2012-08-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Forsberg KJ;Reyes A;Wang B;Selleck EM;Sommer MO;Dantas G
通讯作者：
Dantas G
影响因子：
--
作者：
Deng XJ;Yang WY;Huang YD;Cao Y;Wen SY;Xia QY;Xu P
通讯作者：
Xu P