Self-Assembling Myristoylated Human α-Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection

Abstract

The increasing prevalence of antibacterial resistance globally underscores the urgent need to the update of antibiotics. Here, we describe a strategy for inducing the self-assembly of a host-defense antimicrobial peptide (AMP) into nanoparticle antibiotics (termed nanobiotics) with significantly improved pharmacological properties. Our strategy involves the myristoylation of human alpha-defensin 5 (HD5) as a therapeutic target and subsequent self-assembly in aqueous media in the absence of exogenous excipients. Compared with its parent HD5, the C-terminally myristoylated HD5 (HD5-myr)-assembled nanobiotic exhibited significantly enhanced broad-spectrum bactericidal activity in vitro. Mechanistically, it selectively killed Escherichia coli (E. coli) and methicillin-resistant Staphylococcus aureus (MRSA) through disruption of the cell wall and/or membrane structure. The in vivo results further demonstrated that the HD5-myr nanobiotic protected against skin infection by MRSA and rescued mice from E. coli-induced sepsis by lowering the systemic bacterial burden and alleviating organ damage. The self-assembled HD5-myr nanobiotic also showed negligible hemolytic activity and substantially low toxicity in animals. Our findings validate this design rationale as a simple yet versatile strategy for generating AMP-derived nanobiotics with excellent in vivo tolerability. This advancement will likely have a broad impact on antibiotic discovery and development efforts aimed at combating antibacterial resistance.

Aggregation determines the selectivity of membrane-active anticancer and antimicrobial peptides: The case of killerFLIP

“…Overall, our data indicate that peptide aggregation should be taken into account as an additional method to vary the effective hydrophobicity of membrane-active HDPs, and therefore their cell-selectivity. Peptide aggregation or ordered self-assembly presents additional advantages, since it reduces susceptibility to proteolytic degradation, it affects the pharmacokinetics and pharmacodynamics [72,[79][80][81], and it allows the local release of a high peptide concentration at a single site in the membrane [82][83][84]. Finally, aggregates of membrane-active peptides could be even considered for the entrapment of small-molecule drugs inside the hydrophobic core of the particles, for targeted delivery [85][86], leading to the development of new therapeutic tools based on synergistic effects [87].…”

Enhancing the antibacterial activity of PMAP‐37 by increasing its hydrophobicity

“…Moreover, lung and liver slices (Zhang, Zhou, et al, ) were generated to observe pathological damage. Pathological changes were scored as described previously (Lei et al, ; Wang et al, ; Yufeng et al, ). The therapeutic experiment investigating PMAP‐37 and its analogs in mice infected with S. typhimurium SL1344 was consistent with the above experimental process.…”

Supramolecular Antibacterial Materials for Combatting Antibiotic Resistance

“…Moreover, it is reasonable to conclude that stimuli‐responsive peptides enable regulation of AMPs under specific conditions. In this regard, Lei et al described a combinatorial strategy, involving self‐assembly of a synthetic cationic AMP (myristoylated α‐defensin 5) and myristic acid that leads to significantly improved pharmacologic properties of antibiotics . Wan et al also developed a smart peptide‐based nanogel that has both antibacterial activity and a pH‐response ability .…”