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Title: Synthesis and isolation of biosynthetic derivatives of amphotericin B
Author: Walmsley, Simon Xavier
ISNI:       0000 0004 6494 983X
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2017
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Amphotericin B has been used in the clinic for over fifty years in the treatment of serious fungal infections without any evidence of resistance developing, and recently has also become a frontline treatment for the parasite borne disease leishmaniasis, endemic in many poorer regions of the world. Alternative antibiotics are prone to the pathogens developing resistance, however amphotericin B is highly toxic leading to unpleasant side effects. A less toxic liposomal formulation is expensive limiting its use in the UK NHS and, even with a large WHO subsidy, restricting application to treating leishmaniasis. Semisynthetic modification has led to improved analogues, but at prohibitive cost. This thesis presents work as part of a programme with Dr Caffrey (UCD, Dublin) to use synthetic biology in order to generate in vivo improved analogues of amphotericin B at clinically affordable cost. A promising 16-descarboxyl-16-methyl analogue has been identified by a previous student, but only isolated in very small quantities. An efficient protocol for the isolation of decigram quantities of 16-descarboxyl-16-methyl analogue is developed, along with inexpensive semisynthetic modifications to decrease the haemolytic activity in animal cells. A noted synthetic analogue is the fructosylated disaccharide MFAME (N-methyl-N-D-fructosyl amphotericin B methyl ester), which has improved antifungal and decreased haemolytic properties, but due to the complex synthesis is not economically viable. Caffrey has produced a plasmid which when transfected into S. nodosus bacteria generates a mannosylated disaccharide analogue, the isolation and purification of which is documented in this thesis, along with biological testing where it was discovered to have reduced haemolytic activity compared to the parent molecule.
Supervisor: Rawlings, Bernard ; Cullis, Paul Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available