Combating bacterial infections with host defense peptides: Shifting focus from bacteria to host immunity.

The increasing prevalence of multidrug-resistant bacterial infections necessitates the exploration of novel paradigms for anti-infective therapy. Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), have garnered extensive recognition as immunomodulatory molecules that leverage natural host mechanisms to enhance therapeutic benefits. The unique immune mechanism exhibited by certain HDPs that involves self-assembly into supramolecular nanonets capable of inducing bacterial agglutination and entrapping is significantly important. This process effectively prevents microbial invasion and subsequent dissemination and significantly mitigates selective pressure for the evolution of microbial resistance, highlighting the potential of HDP-based antimicrobial therapy. Recent advancements in this field have focused on developing bio-responsive materials in the form of supramolecular nanonets. A comprehensive overview of the immunomodulatory and bacteria-agglutinating activities of HDPs, along with a discussion on optimization strategies for synthetic derivatives, is presented in this article. These optimized derivatives exhibit improved biological properties and therapeutic potential, making them suitable for future clinical applications as effective anti-infective therapeutics.

Biomimetic Peptide Nanonets: Exploiting Bacterial Entrapment and Macrophage Rerousing for Combatting Infections.

The alarming rise in global antimicrobial resistance underscores the urgent need for effective antibacterial drugs. Drawing inspiration from the bacterial-entrapment mechanism of human defensin 6, we have fabricated biomimetic peptide nanonets composed of multiple functional fragments for bacterial eradication. These biomimetic peptide nanonets are designed to address antimicrobial resistance challenges through a dual-approach strategy. First, the resulting nanofibrous networks trap bacteria and subsequently kill them by loosening the membrane structure, dissipating proton motive force, and causing multiple metabolic perturbations. Second, these trapped bacterial clusters reactivate macrophages to scavenge bacteria through enhanced chemotaxis and phagocytosis via the PI3K-AKT signaling pathway and ECM-receptor interaction. In vivo results have proven that treatment with biomimetic peptide nanonets can alleviate systemic bacterial infections without causing noticeable systemic toxicity. As anticipated, the proposed strategy can address stubborn infections by entrapping bacteria and awakening antibacterial immune responses. This approach might serve as a guide for the design of bioinspired materials for future clinical applications.

Unlocking Antibacterial Potential: Key-Site-Based Regulation of Antibacterial Spectrum of Peptides.

In the pursuit of combating multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as promising agents; however, their application in clinical settings still presents challenges. Specifically, the exploration of crucial structural parameters that influence the antibacterial spectrum of AMPs and the subsequent development of tailored variants with either broad- or narrow-spectrum characteristics to address diverse clinical therapeutic needs has been overlooked. This study focused on investigating the effects of amino acid sites and hydrophobicity on the peptide's antibacterial spectrum through Ala scanning and fixed-point hydrophobic amino acid substitution techniques. The findings revealed that specific amino acid sites played a pivotal role in determining the antibacterial spectrum of AMPs and confirmed that broadening the spectrum could be achieved only by increasing hydrophobicity at certain positions. In conclusion, this research provided a theoretical basis for future precise regulation of an antimicrobial peptide's spectrum by emphasizing the intricate balance between amino acid sites and hydrophobicity.

Characterization of simplified nonapeptides with broad-spectrum antimicrobial activities as potential food preservatives, and their antibacterial mechanism.

Antimicrobial peptides (AMPs) have attracted attention in the field of food preservatives due to their favorable biosafety and potential antimicrobial activity. However, high synthetic cost, systemic toxicity, a narrow antimicrobial spectrum, and poor antimicrobial activity become the main bottlenecks for their practical applications. To address these questions, a set of derived nonapeptides were designed based on a previously discovered ultra-short peptide sequence template (RXRXRXRXL-NH2) and screened to identify an optimal peptide-based food preservative with excellent antimicrobial properties. Among these nonapeptides, the designed peptides 3IW (RIRIRIRWL-NH2) and W2IW (RWRIRIRWL-NH2) presented a membrane-disruptive and reactive oxygen species (ROS) accumulation mechanism to execute potent and rapid broad-spectrum antimicrobial activity without observed cytotoxicity. Moreover, they exhibited favorable antimicrobial stability regardless of high ionic strength, heat, and excessive acid-base conditions, retaining potent antimicrobial effects for chicken meat preservation. Collectively, their ultra-short sequence length and potent broad-spectrum antimicrobial capacity may be beneficial for the further development of green and safe peptide-based food preservatives.

Self-Assembly of Antimicrobial Peptide-Based Micelles Breaks the Limitation of Trypsin.

Targeting the limitation of antimicrobial peptides (AMPs) application in vivo, self-assembled AMPs library with specific nanostructures is expected to gradually overtake monomer AMPs libraries in the future. Peptide polymers are fascinating self-assembling nanoscale structures that have great advantage in biomedical applications because of their satisfactory biocompatibility and versatile properties. Herein, we describe a strategy for inducing the self-assembly of T9W into nanostructured antimicrobial micelles with evidently improved pharmacological properties, that is, PEGylation at the C-terminal of T9W (CT9W1000), an antibacterial biomaterial that self-assembles in aqueous media without exogenous excipients, has been developed. Compared with parental molecular, the CT9W1000 is more effective against Pseudomonas aeruginosa, and its antibacterial spectrum had also been broadened. Additionally, CT9W1000 micelles had higher stability under salt ion, serum, and acid-base environments. Importantly, the self-assembled structure is highly resistant to trypsin degradation, probably allowing T9W to be applied in clinical settings in the future. Mechanistically, by acting on membranes and through supplementary bactericidal mechanisms, CT9W1000 micelles contribute to the antibacterial process. Collectively, CT9W1000 micelles exhibited good biocompatibility in vitro and in vivo, resulting in highly effective treatment in a mouse acute lung injury model induced by P. aeruginosa PAO1 without drug resistance. These advances may profoundly accelerate the clinical transformation of T9W and promote the development of a combination of peptide-based antibiotics and PEGylated nanotechnology.

Microglia Polarization: A Novel Target of Exosome for Stroke Treatment.

The vast majority of cells in the human body are capable of secreting exosomes. Exosomes have become an important vehicle for signaling between cells. Exosomes secreted by different cells have some of the structural and functional properties of that cell and thus have different regulatory functions. A large number of recent experimental studies have shown that exosomes from different sources have different regulatory effects on stroke, and the mechanisms still need to be elucidated. Microglia are core members of central intrinsic immune regulatory cells, which play an important regulatory role in the pathogenesis and progression of stroke. M1 microglia cause neuroinflammation and induce neurotoxic effects, while M2 microglia inhibit neuroinflammation and promote neurogenesis, thus exerting a series of neuroprotective effects. It was found that there is a close link between exosomes and microglia polarization, and that exosome inclusions such as microRNAs play a regulatory role in the M1/M2 polarization of microglia. This research reviews the role of exosomes in the regulation of microglia polarization and reveals their potential value in stroke treatment.