Synthesis of Teixobactin Analogues: Cyclic Peptidomimetics to Combat Antibiotic Resistance

The development of bacterial resistance over time combined with the lack of novel compounds has resulted in a drastic need for new antibiotic drugs. The structure of teixobactin, a cyclic undecapeptide, was published in January 2015 in a paper describing the use of an “iChip” to successfully grow a number of previously uncultivable bacteria. Teixobactin, a cyclic depsipeptide made up of 11 amino residues, containing the unproteinogenic amino acid L-alloenduracididine, was found to have μM activity against many Gram-positive bacteria, including Clostridium difficile and methicillin-resistant Staphylococcus aureus (MRSA). This research aimed to both further elucidate the mechanism of action of teixobactin by examining the structure-activity relationship of various moieties of the compound; and to create related compounds that could be synthesised simply and economically, whilst retaining potency against Gram-positive bacteria. These focused particularly on investigating the role of residues 1-7; the linear hydrophobic tail, and variation of the nonproteinogenic residue by replacement with genetically encoded variants. To form the native macrocycle, a simple synthetic route towards L-allo-enduracididine was required; a novel route using Ni(II) Schiff base complex was attempted. The formation of the 13-membered macrocyclic core of teixobactin was attempted with multiple methods of cyclisation, using both solution-phase and on-resin approaches, ultimately resulting in an effective route providing 100% conversion of linear precursors in 20 minutes. Nineteen analogues were synthesised and submitted for biological assays. These compounds were acetylated, prenylated or lipidated in place of residues 1-7, with L-allo-enduracididine mutated to seven different residues varying in functionality, basicity and structure. Of the compounds tested, four were found to have antibiotic activity, with one compound displaying high potency with a minimum inhibitory concentration (MIC) value (0.5 μg/ mL), comparable to native teixobactin itself.