Today, we are sharing a review article published in Nature Reviews Microbiology, co-authored by Nelson G. Oliveira Junior et al., which systematically summarizes the research progress on antimicrobial peptides (AMPs), with a focus on their potential as novel therapeutics to address the global antibiotic resistance crisis. The article highlights that AMPs, owing to their structural diversity, multi-mechanistic actions, and eco-friendly properties (e.g., biodegradability), represent promising alternatives. However, clinical translation still faces challenges such as stability issues, reduced in vivo activity, toxicity, and bacterial resistance. The review comprehensively covers the widespread occurrence of AMPs, their structural classification, mechanisms of action, and bacterial resistance mechanisms. It further discusses optimization strategies through computational design and chemical modifications, and finally outlines translational prospects in human and animal health, emphasizing the role of emerging technologies like artificial intelligence in accelerating AMP discovery. The following analysis will delve into key aspects: structure, mechanisms, resistance, design strategies, and applications.
1. Structural Diversity of AMPs
The structure of AMPs underpins their function. The article categorizes AMPs into four classes: linear extended structures, helical structures, β-sheet structures, and mixed α/β motifs. Linear AMPs (e.g., indolicidin) lack fixed secondary structures and rely on membrane interactions; helical AMPs (e.g., magainin) form amphipathic helices via hydrogen bonding, facilitating membrane penetration; β-sheet AMPs (e.g., gomesin) are stabilized by disulfide bonds, enhancing stability; and mixed-structure AMPs combine the flexibility of α-helices with the rigidity of β-sheets, reducing resistance risks. Additionally, cyclic AMPs (e.g., cyclotides) form closed loops via covalent bonds, improving resistance to protease degradation. This structural diversity enables AMPs to attack pathogens through multiple mechanisms but also increases the complexity of design and optimization.
2. Mechanisms of Action and Targets
AMPs act not only through membrane disruption but also via intracellular targets. Membrane disruption involves models such as the barrel-stave, carpet, and toroidal pore mechanisms, which depend on electrostatic interactions with negatively charged bacterial membranes. For instance, magainin induces membrane curvature via the toroidal pore model, leading to content leakage, while aurein 1.2 disrupts membrane integrity through a detergent-like carpet mechanism. Beyond membrane targets, AMPs can inhibit intracellular processes such as protein synthesis (e.g., drosocin binding to ribosomes), DNA/RNA replication (e.g., buforin interfering with nucleic acid phase transitions), and enzyme activity (e.g., lactoferricin inhibiting arginine decarboxylase). The article also highlights emerging targets like the LPS transport system (Lpt) and the β-barrel assembly machinery (BAM), where peptides such as zosurabalpin and darobactin specifically inhibit these systems, reducing host cell toxicity.
Fig. 1 | Structures, mechanisms of action and distinctive targets of AMPs.
3. Mechanisms of Antimicrobial Resistance
Bacterial resistance to AMPs includes intrinsic, adaptive, and acquired resistance. Intrinsic resistance stems from structural features like outer membrane impermeability; adaptive resistance is transient and reversible, triggered by environmental stress (e.g., sublethal AMP concentrations) and involves membrane modifications or efflux pump overexpression; acquired resistance arises via genetic mutations or horizontal gene transfer. Common mechanisms include membrane charge alterations (e.g., Ara4N or PEtN additions to LPS), biofilm formation, AMP sequestration by outer membrane vesicles, and protease degradation (e.g., by ClpXP and OmpT). The article emphasizes that cross-resistance can occur between AMPs but is not universal—e.g., temporin-resistant strains may show cross-resistance to other AMPs, whereas no cross-resistance exists between melittin and pexiganan. This underscores the need for careful selection of AMP combinations in therapy to minimize resistance risks.
4. AMP Design and Optimization Strategies
To overcome AMP limitations, the article outlines various design and optimization strategies. Computational tools (e.g., evolutionary algorithms and machine learning) predict and optimize AMP sequences—e.g., temporin-Ali’s activity was enhanced 160-fold via genetic algorithms. Stability-enhancing methods include cyclization, N-terminal modifications, D-amino acid incorporation, or unnatural amino acids to improve protease resistance. Hybrid strategies combine elements of different AMPs; for example, R7 AMP uses cleavable linkers to enhance activity and specificity. Self-assembly approaches enable AMPs to form nanostructures (e.g., dendrimers or micelles), prolonging in vivo half-life and increasing local concentration. These methods not only improve efficacy but also reduce toxicity and resistance development.
Fig. 2 | AMP design strategies and modifications.
5. AMPs as Therapeutic Innovations
In translational medicine, AMPs have entered clinical trials, though most are limited to topical applications (e.g., wound infections or keratitis) due to challenges in systemic delivery (e.g., protease degradation and plasma protein binding). The article cites several clinical candidates, such as PL-5 (for wound infections), Melimine (for keratitis), and Tilapia piscidin 4 (for soft tissue infections). While some AMPs (e.g., Neuprex) failed in Phase III trials due to insufficient efficacy or toxicity, these experiences highlight the need for better selectivity and delivery systems. The article also notes AMP applications in veterinary medicine, such as using piscidin or lactoferricin in poultry and swine to improve gut health and reduce antibiotic use. Future advances may enable safer systemic applications via structural modifications (e.g., PEGylation) and nanotechnology-based delivery systems.
6. Prospects and Conclusions
The review concludes that AMP research must further explore novel structural classes and targets to combat antibiotic resistance. AI and machine learning accelerate AMP discovery—e.g., through "molecular de-extinction" strategies mining peptides from extinct organisms. Self-assembling nanostructures, cyclic peptides, and multifunctional hybrids represent future directions, but clinical translation requires balancing potency, toxicity, and stability. The article emphasizes that AMPs hold promise not only in human medicine but also in agriculture and veterinary fields, contributing to sustainable global health.
In summary, this review provides a comprehensive overview of AMPs’ journey from basic science to clinical translation, highlighting structural diversity, mechanistic complexity, and design innovations. It serves as a key reference for developing next-generation antimicrobial therapies. By integrating multidisciplinary approaches, AMPs are poised to play a critical role in addressing resistance challenges.
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