Peptaibiotic-inspired antimicrobials based on human cathelicidin

Mammalian cell toxicity of human host defense peptides (HDPs) is a key factor limiting the development of new antibiotic classes based on these natural product templates. In recent work, we have reported both residues in the human cathelicidin LL-37 that reduce its toxicity and strategies for enhancing the potency of short derivatives of LL-37 through mimicry of the LL-37 N-terminus. Here we describe structure-activity relationship studies of one such short derivative, FF-14, in which structure and ultimately separation of hemolytic and antimicrobial functions are supported via the mimicry of Aib-rich peptaibiotic natural products.