Multifunctional cyclic biomimetic peptides: Self-assembling nanotubes for effective treatment of sepsis

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.