Design and synthesis of Acyldepsipeptide-1 analogues: Antibacterial activity and cytotoxicity screening

Acyldepsipeptides (ADEPs) are receiving more attention as prospective antimicrobial agents due to their unique mode of action and chemical properties. However, their therapeutic potential is limited by their poor pharmacokinetic properties. Chemical modifications have been successful in improving the biocompatibility and bioavailability of ADEPs. In the current study, ADEP1 was modified by introducing a disulphide linkage, replacement of the octa-2,4,6-trienoic acid (OTEA) with either adamantane (Ada) or palmitic acid (Pal), and lastly, comparing the use of D versus L amino acids. The antibacterial effects of the ADEP1 analogues were investigated in Gram-positive and Gram-negative strains using agar well diffusion and microdilution assays. Cytotoxicity was evaluated in human embryonic kidney (HEK)-293 and colon cancer (Caco-2) cells by the MTS assay. Using solid phase peptide synthesis (SPPS), the percentage yield of the synthetic peptides was increased to > 37% with > 96% purity. The anionic ADEP1 analogues demonstrated a broad-spectrum antibacterial activity. Although the ADEP1 analogues did not display the expected antibacterial activity in relation to the parent structure, they were not cytotoxic against the tested cell lines. This study proved that biocompatibility of natural ADEPs can be improved by modifying some of its chemical groups. Further studies are required to enhance the antibacterial activity of the ADEP1 analogues either by structural modifications or through supplementation of these anionic antimicrobial peptides (AMPs) with divalent metal ions.