Design Synthesis and Antimicrobial Evaluation of Structurally Diverse Short Peptide Based Molecules

Abstract

The nearexplosive increased occurrence in multidrug resistant pathogens is recognized as a severe threat to public health in nations around the globe. AMPs are being considered as a potential source of novel peptide based antibiotics because of their numerous advantages such as broadspectrum activity lower tendency to induce resistance immunomodulatory response and especially their unique mode of action. In spite of these striking features AMPs are not ideal drug candidates due to unfavourable pharmacokinetics owing to proteolytic degradation potential immunogenicity and toxicity. Furthermore AMPs have high production cost as amino acids are expensive building blocks. This may also severely restrict their commercial production as peptide based antibiotic. To address these problems associated with AMPs the research work described here is aimed to develop novel peptide based biocompatible antimicrobial agents. newlineWe have rationally designed and successfully synthesized a library of short abiotic lipopeptides by varying both cationic charge and hydrophobic content with aim to identify the minimum structural requirements for antimicrobial activity. Most of the synthesized lipopeptides displayed broad activity spectrum against susceptible as well as antibiotic resistant clinical isolates of bacteria and fungi. The most potent lipopeptide LP16 has MICs in the range of 1.56.25 and#956;g/mL against all tested Grampositive Gramnegative bacterial strains. Maximum antifungal activity was observed for LP24 with MICs in the range of 1.54.5 µg/mL. The hemolytic and MTT assay results revealed the lower cytotoxicity of lipopeptides toward mammalian cells. By systematic analysis of the activity results of lipopeptides we found that three ornithine residues conjugated with myristic acid is minimum requirement for a compound to be an antimicrobial agent. Results of calcein dye leakage experiments suggests the membranolytic effect of lipopeptides.