Replacing L-Amino Acid with D-Amino Acid Residues On An Ultrashort Cationic Lipopeptide To Improve Anti-microbial Activity

Academic Pit

With the overuse, and misuse, of antibiotics, bacteria have become resistant to most commercial drugs. Hence, there is a need to develop new classes of antimicrobial agents. This project aims to evaluate if incorporating D-amino acid residues will improve the antimicrobial activity of lipopeptides. A known antimicrobial agent, Myr-L-(orn)3-NH2 and its mirror-image, myr-D-(orn)3-NH2, were synthesized on a Rink-amide resin using the Fmoc solid phase synthesis strategy. The UV spectra of the Fmoc deprotection solutions confirmed that the Fmoc protecting group was released on each stage of deprotection. Major peaks around 21.6 - 21.8 minutes were observed in the HPLC profiles of the crude lipopeptides. Purification of the desired fractions was achieved by preparative HPLC using a reverse phase column. Mass spectrometry confirmed that the target lipopeptides were successfully synthesized with [M+H+] at 570 and [M+H+Na+] at 593. Circular dichroism data displayed positive and negative peaks distinguishing the enantiomers. The D-lipopeptide was observed to have better antimicrobial activity in S. aureus than in E. coli, with MIC of 12.5 μg/ml and 25 μg/ml respectively. However, the D-isomer it was slightly less active than the L-lipopeptide. Nevertheless, these results verify that lipopeptides kill bacteria through non-specific interaction, unlike drugs that bind to specific enzymes. These enantiomeric lipopeptides have shown potential as drugs.