The emergent resistance of bacteria against the conventional antibiotics has motivated the search for novel antimicrobial agents. Nature abounds with a number of host defense peptides (HDPs). HDPs are present in virtually all life forms, acting as the first line of defence against microbial infection. While they are  broad-spectrum in their activity and show less drug-resistance induction, their intrinsic metabolic stability limits their potential therapeutic applications. We have previously reported a group of unnatural HDP mimics, a-AApeptides (N-a cylated-N-a minoethyl peptides), as effective antimicrobial agents against various bacterial strains. Herein, we report the development of modified a-AApeptides, through simultaneous lipidation and cyclization. These novel cyclic lipo-a-AApeptides demonstrate significantly improved potency and broad-spectrum activity against a range of clinically relevant Gram-positive and Gram-negative bacteria. Furthermore, the lead cyclic lipo-a-AApeptide is the first of its kind shown to mimic some HDPs by  antagonizing TLR4-induced nuclear factor kappa-light-chain-enhancer of activated B cells (NF-?B) and nitric oxide (NO) signaling responses, as well as inhibiting production of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a). The linear analogue of the lead cyclic lipo-a-AApeptide shows weaker antimicrobial and inferior anti-inflammatory activity, indicating that both lipidation and cyclization are critical for the dual functions. Our results suggest that these cyclic lipo-a-AApeptides may emerge as a new class of antibiotic agents with both direct bacterium killing and immunomodulation ability.

Antimicrobial cyclic lipo-a-AApeptides

247th National Meeting (2014)

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