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Title: Approaches to natural product antibiotic discovery from actinomycetes
Author: Chrobak, Olga Maria
ISNI:       0000 0004 7429 9914
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2018
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The problem of increasing emergence of antibiotic resistance coupled to a decrease in the discovery rate of new antibiotics has been recognised as a worldwide health threat. One of the solutions to this problem is discovery of novel antibiotics and new antibiotic classes. Natural product (NP) antibiotic discovery from actinomycetes is a well-established approach which yielded many clinically relevant drugs and has received an increasing interest in the recent years due to modern technological advancements. This study was set out to investigate several approaches to NP antibiotic discovery from actinomycetes with the aim to identify the success rate of each, propose a new approach and potentially discover novel NP antibiotics. In chapters 3 and 4, the Waksman platform to NP antibiotic discovery was investigated, enhanced with bioactivity dereplication screens against multi-drug resistant (MDR) bacteria and selection of taxonomically novel Streptomyces spp. Although the process proved time- consuming and yielded known compounds, two putatively new derivatives from a known antibiotic class of streptophenazines (produced by strain DEM20663) were identified. In chapter 5 genome analysis of DEM20663 focusing on biosynthetic gene clusters (BGCs) responsible for the antibiotic activity identified in the previous chapters was performed. Two previously uncharacterised BGCs encoding a type II PKS and a phenazine derived NP antibiotics were identified. Based on the genomic data, the biosynthetic pathways for both groups of compounds were suggested and the structures of two putatively novel streptophenazine derivatives were proposed. Heterologous expression of two orphan BGCs as predicted by bioinformatic analysis was discussed in chapter 6. With no a priori knowledge of the resulting NPs, the attempts to express two BGCs from a novel Amycolatopsis sp. in Streptomyces coelicolor M1152 and M1154 hosts resulted in purification of a putatively novel NP of a BGC encoding an iterative type I polyketide synthase. In chapter 7 an integrated “omics” approach to NP antibiotic discovery was proposed. Based on integrating data from genomic, transcriptomic and metabolomic studies fifteen prioritised actinomycete strains were examined. Although this resulted in a number of known NP antibiotics, a putatively novel lantibiotic was identified using the integrated “omics” approach.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available