Nonribosomal E-vinylogous γ-amino acids are widely present in many peptide natural products and have been exploited as inhibitors for serine and cysteine proteases. Here, we are reporting the broad spectrum antimicrobial properties and self-assembled nanostructures of various hybrid lipopeptides composed of 1:1 alternating α- and E-vinylogous residues. Analysis of the results revealed that self-assembled nanostructures also play a significant role in the antimicrobial and hemolytic activities. In contrast to the α-peptide counterparts, vinylogous hybrid peptides displayed excellent antimicrobial properties against various bacterial and fungal strains. Peptides that adopted nanofiber structures displayed less hemolytic activity, while peptides that adopted nanoneedle structures displayed the highest hemolytic activity.

A facile, efficient and racemization-free method for the synthesis of N-protected β-amino alcohols and peptaibols using N-hydroxysuccinimide active esters is described. Using this method, dipeptide, tripeptide and pentapeptide alcohols were isolated in high yields. The conformations in crystals of β-amino alcohol, dipeptide and tripeptide alcohols were analysed, with a well-defined type III β-turn being observed in the tripeptide alcohol crystals. This method is found to be compatible with Fmoc-, Boc- and other side-chain protecting groups.

Utilization of conjugated double bonds to engineer the novel folded miniature β-meander type structures, single step transformation of miniature β-meanders into ααγ(4)-hybrid peptide 10/12-helices using catalytic hydrogenation, their solution and single crystal conformations are reported.

Herein we report the potent antimicrobial activity of α,γ-hybrid lipopeptides composed of 1:1 alternating α- and γ-amino acids. Along with their potent antimicrobial activity against various Gram-positive and Gram-negative bacteria, these hybrid lipopeptides were found to be less hemolytic. Studies into the mechanism of action revealed that these short cationic lipopeptides bind and disrupt the bacterial cell membrane. Time-kill kinetics analyses revealed that the potent α,γ-hybrid lipopeptides completely inhibit bacterial growth in less than 20 minutes. Overall, the promising antimicrobial activity along with lower hemolytic activity displayed by these α,γ-hybrid lipopeptides make them well suited for further exploration into the design of potent lipopeptide antibiotics.