The discovery of antibiotics has played a significant role in raising public health standards and improving the outcomes for patients with bacterial infections. Unfortunately, drug discovery efforts have not kept pace with emergence and spread of antibiotic resistance. This project is part of a discovery programme designed to assess the metabolic potential of Actinoallomurus, a recently described genus within the Actinobacteria. The schedule of work included small-scale fermentations (from 200 strains) followed by bioactivity testing. The most promising positive samples were then subjected to a combination of bioassays with chemical analyses to determine the chemical identity of the active compounds, with the objective of finding novel antibiotics. The Results section is organized in four different but closely related chapters. These present Actinoallomurus as a potential new source for active metabolites. Firstly, by showing, in a sample of around 200 strains, over 40% inhibited antimicrobial growth in the conditions tested but also by adding to the elevated quantity of positive hits a high degree of diversity, with the major biosynthetic pathways being identified whether in the molecules screened or also in the genomes analysed. To illustrate not only the type of metabolites produced by Actinoallomurus, but also the multidisciplinary of Drug Discovery expeditions three chapters characterizing new compounds are presented followed by a genomic characterization of four Actinoallomurus Strains. These three chapters show how the delivery of new potential drug candidates demands an always broader set of diverse tools to be applied. While the three new molecules support not only the ability of Actinoallomurus to produce interesting active metabolites, but also the importance that a proper strain library plays in drug discovery, the genomic analyses predict, as for many other actinomycetes, an even brighter future, since the genetic potential for producing bioactive molecules surpasses the compounds that can be detected under routine cultivation conditions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:694620 |
| Date | January 2016 |
| Creators | Cruz, João Carlos Santos |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/81849/ |
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