Turing cationic antimicrobial peptide KR-12 into Self-assembled nanobiotics with potent bacterial killing and LPS neutralizing activities

Abstract

Abstract Gram-negative sepsis has become one of major increasing medical burdens globally, which is subjected to growing antibiotic resistance problem and the relatively delayed development of new antibiotics. LL-37, the only type of Cathelicidin identified in humans, has diverse biological activities including direct bactericidal action, regulation of inflammation and LPS-neutralization. The KR-12 peptide is the smallest portion of LL-37 with antibacterial action, which has been shown that could be modified into more effective antimicrobials. Here, we synthesize two myristoylated derivatives of KR-12, Myr-KR-12N and Myr-KR-12C, which can spontaneously form nanoparticles when mixed with deionized water. We show that myristoylated KR-12 derivatives possess a broad-spectrum and more powerful bactericidal activity through interrupting the membranes of bacteria. Myr-KR-12N rescues mice from lethal sepsis induced by E. coli, even more potent rescuing activity than meropenem. We also demonstrate that myristoylated KR-12 nanobiotic can significantly bind with LPS and inhibit the inflammation in vitro and Myr-KR-12N rescue mice from LPS-induced sepsis in vivo, even more potent rescuing activity than polymyxin B. Toxic experiments indicate that neither Myr-KR-12N nor Myr-KR-12C nanobiotics exhibits meaningful hemolytic activity, liver and kidney injury. We thus developed a novel nanobiotic with dual bactericidal and LPS-neutralization properties, which may provide good insights for clinical translation of antimicrobial peptides and the creation of new antibiotics.