Abstract
ABSTRACTThe world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria.
Highlights
The lack of TLR3 signaling by the nonhuman cathelicidins was due to the inability to use the formyl peptide receptor-like receptor 1 to endocytose the doublestranded RNA⫺LL-37 complex and deliver the poly(I·C) to TLR3 in endosomes [17]
We demonstrate that cathelicidins produced by animals can have an array of activities to modulate proinflammatory TLR signaling in human cells, to suppress inflammation by bacterial ligands, and to kill bacteria
Two cathelicidins from sheep and cows were identified to have a combination of activities that hold promise to treat Gram-negative bacterial infection
Summary
LL-37 had the least potent antibacterial activity of the cathelicidins tested, requiring at least 32 g/ml to inhibit the growth of any of the 19 bacterial strains (Table 1). The removal of the eight amino acids that includes the intrinsically disordered C-terminal tail of LL-37, resulting in LL-29, reduced hRBC lysis [19] (Fig. 3). These results suggest that the intrinsically disordered C-terminal tails in the cathelicidins mbio.asm.org contributed to hRBC lysis but not the antibacterial activity of the peptides.
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