Isolation and semi-synthesis of enterocin analogues as novel antibiotics

Enterocin, a uniquely-structured polyketide, was first isolated in 1976 from two soil Streptomyces with reported broad-spectrum bacteriostatic activity. In this thesis, the chemical and biological properties of enterocin were re-investigated for its suitability as a next-generation antibiotic scaffold. Importantly, enterocin was found to be less stable than previously reported, undergoing a facile intramolecular rearrangement to a novel polycyclic ketal isomer bereft of antibacterial activity. Enterocin also undergoes further, undocumented degradation under neutral and basic conditions in a range of solvents at room temperature. Semi-synthetic derivatisation of enterocin at its carbonyl and secondary hydroxy positions yielded five new analogues with improved stabilities, albeit with reduced antibacterial activities. These analogues may have applications as pro-drugs to increase the antibiotic bioavailability and half-life. Furthermore, a microbial biodiscovery study was conducted to investigate the co-metabolite profile of an enterocinproducing culture, Streptomyces sp. MST-MA9095. Six α-pyrones related to enterocin were isolated from the culture on an optimised culture medium, four of which showed moderate antibacterial activities against Micrococcus luteus. Preliminary investigations into the mode of action of enterocin suggest that its true ecological role may not be as an antibiotic, but rather as a first-in-class broad-spectrum regulator of secondary metabolite production of other microorganisms.