Antibiotic abuse has led to an increasingly serious risk of antimicrobial resistance, developing alternative antimicrobials to combat this alarming issue is urgently needed. Rhesus theta defensin-1 (RTD-1) is a theta-defensin contributing to broad-spectrum bactericidal activity via the mechanisms of membrane perturbation. Intriguingly, human defensin-6 (HD6), an enteric defensin secreted by Paneth cells without direct bactericidal effect, could self-assembled into fibrous networks to trap enteric pathogens for assistance of innate immunity. The direct bactericidal action of RTD-1 and the bacterial trapping of HD6 inspire a promising antimicrobial paradigm for unique antibacterial strategies. In this study, we utilized the principle of alternating arrangement of D- and L-amino acids in cyclic peptides, which endows them with the potential to self-assemble into nanotubes, mimic the antimicrobial processes of RTD-1 and HD6. We designed and synthesized five cyclic biomimetic peptides (CBPs), among these biomimetics, CBP-4, which possessed a nanotube-like structure, demonstrated the ability to directly and rapidly disrupt the cell membranes of Gram-positive S. aureus and MRSA, while also targeting the surfaces of Gram-negative E. coil using its nanofibrous network to capture bacteria, preventing invasion and migration, and indirectly killing the bacteria. Moreover, CBP-4 eliminated pathogens, inhibited excessive inflammatory responses caused by infections, and maintained immune system homeostasis in septic mice. By fully emulating the antimicrobial mechanisms of both RTD-1 and HD6, CBP-4 showed promising potential for anti-infectious therapies.
Keywords: Biomimetics; Cyclic peptide; Defensin; Nanotubes; Sepsis.
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