Towards knowledge-based bioprospecting of deep-sea sponges

Abstract

Antibiotic resistance is a global threat to human health and our modern healthcare system. Identifying new antibiotics is an important part of the response to this threat, but the current discovery pipeline is woefully inadequate for the expected demand. Historically antibiotics have been obtained by the functional screening of microorganisms, and returning to this approach could yield the next generation of antimicrobials. However, the rediscovery of known compounds remains a significant issue. It has been suggested that exploring extreme environments, such as the deep-sea, may reduce rediscovery rates by enabling access to novel metabolic adaptations in unexplored taxa. This thesis investigates this hypothesis by bioprospecting the microbiota of a unique collection of deep-sea sponges from sites across the Atlantic.

Almost 900 strains of deep-sea bacteria have been cultured and preserved in a culture collection held at the University of Bristol. In this thesis, the strain collection was screened for antibacterial activity, successful ‘hits’ were then genome sequenced to identify the bacterial source. In this way, several novel species of deep-sea bacteria were characterized and found to have potent antibiotic activity, including new species of Micromonospora and Bacillus. Building upon this work, the thesis then explores the utility of metataxonomic ‘pre-screening’, whereby the microbial communities of deep-sea sponges are characterised in advance of culturing to improve the efficiency of screening experiments. The results suggest that pre-screening has poor predictive power for biodiscovery. Finally, the method of ‘ribosome engineering’ was employed to activate silent gene clusters in the novel deep-sea species Streptomyces ortus sp. nov. and M. ferruginea sp. nov. Mutant strains of both bacteria were found to alter their natural product profile; this included the enhanced biosynthesis of several unknown bioactive compounds as well as a significant increase in a particular anthracycline family, the cinerubins, in S. ortus. The implications of these results for future antimicrobial discovery are discussed.

Date of Award	12 May 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Paul Curnow (Supervisor) & Paul R Race (Supervisor)