Antimicrobial peptides: Application informed by evolution

Small-molecule defense Small-peptide defense molecules are produced by most organisms to fend off invasion by bacteria. The antimicrobial peptides that we know about so far show substantial diversity, synergism, and alternative functions. Lazzaro et al. review our knowledge of the evolution and diversity of antimicrobial peptides, the rapid pharmacodynamics of which make them promising candidates for translational applications to complement efforts to overcome antibiotic resistance. Science, this issue p. eaau5480 BACKGROUND 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. ADVANCES 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. OUTLOOK 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. 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. CREDIT: BEE ILLUSTRATION BY MELISSA BROUSSARD/PHYLOPIC/CC 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.