Synthesis of peptide antibiotics for Mycobacterium tuberculosis

• Main Author: Lin, Hong Xuan
• Other Authors: Roderick Wayland Bates
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Chemistry; Medicine, Health and Life Sciences; Tuberculosis; Antibiotics; Antimicrobial resistance; Peptides; Antimicrobial peptides; ATP synthase inhibitor
• Online Access: https://hdl.handle.net/10356/175109
• Institution: Nanyang Technological University

Many drug candidates against TB fail in an early stage during primary screening. While they were discovered to be effective enzyme inhibitors, this did not always translate to effective inhibitors of bacterial growth. The primary reason for this is that the thick, hydrophobic cell wall of M. tuberculosis (Mtb) acts as a barrier to the entry of drug molecules. Such was the case for EpMF2, a hit compound that was discovered via virtual screening as an inhibitor of the ε subunit of the F1FO ATP synthase. Analogues of EpMF2 have been synthesized that were effective inhibitors of M. smegmatis F1FO ATP synthase in IMVs but all failed to inhibit growth of live M. smegmatis. To get around this problem a prodrug strategy was devised using cholesterol as a carrier. Mtb has an affinity to cholesterol and tends to incorporate cholesterol into itself during infection of macrophages. The concept behind the prodrug idea is to induce the bacterium to ingest the cholesterol-EpMF2 conjugate, where EpMF2 would be released in the cytosol after cleavage of the molecule and kill it. Several cholesterol-EpMF2 conjugates were synthesized and underwent assay testing, and some were able to inhibit growth of M. smegmatis. This proved the viability of the cholesterol prodrug concept in principle as a method to penetrate the mycobacterial bacterial cell wall, but more work needs to be done to optimize this delivery method, particularly the poor aqueous solubility of the conjugates. Chapter 1 will provide a brief review of the various types of prodrug chemical structures and activation methods, with a focus on real life examples currently being used or in development. Chapter 2 describes the discovery, synthesis, and assay tests of EpMF2 and its analogues, and an investigation to its structural-activity relationship. Chapter 3 describes the conception of the cholesterol prodrug idea, the synthesis of EpMF2-cholesterol conjugate compounds, and its assay tests. The final chapter will briefly touch upon future work that can be done based on the findings in Chapter 3.