Development of a biofilm penetrant delivery system for oligonucleotide-based antimicrobials to treat Burkholderia pseudomallei infections

Pattinson, Adam (2022) Development of a biofilm penetrant delivery system for oligonucleotide-based antimicrobials to treat Burkholderia pseudomallei infections. Doctoral thesis, University of East Anglia.

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Abstract

Burkholderia pseudomallei is the etiological agent of melioidosis, a tropical disease that infects around 165,000 people annually and results in approximately 89,000 deaths. The current treatment regime employs a biphasic approach consisting of intravenous meropenem or ceftazidime followed by oral co-trimoxazole or co-amoxiclav. Despite this, mortality still occurs in up to 40% of cases. Due to its high aerosol infectivity, the ability to present as an aggressive disease with non-specific symptoms, and the lack of rapidly scalable treatment, B. pseudomallei is classified as a biothreat agent by the Centre of Disease Control and the National Institute for Allergy and Infectious Disease. Hence, there is a need for novel treatment approaches.

Transcription factor decoys (TFDs) are oligonucleotide-based antimicrobials that selectively inhibit bacterial transcription factors that are essential for viability and virulence. 12-bis-THA is a lipophilic cation that self-assembles to form particles that bind TFDs with high affinity and protect them from enzymatic degradation. These particles deliver TFDs to the cytoplasm of Gram-positive and Gram-negative bacteria through electrostatic and lipophilic interactions with prokaryote-specific membrane components. This technology is an attractive platform for antimicrobial development as it acts on novel targets and circumvents traditional antimicrobial resistance mechanisms whilst sparing the host microbiota.

In this thesis, we examine whether 12-bis-THA is capable of delivering TFD antimicrobials through the capsulated cell wall, and the biofilms of B. thailandensis strain E555. As 12-bis-THA is endowed with antimicrobial activity, an integrative proteomic and metabolomic study was performed to provide insight into its mechanism of action and to identify candidates for TFD development. This was performed in along with a literature search to identify alternative candidates that were conserved in multiple Burkholderia species including B. pseudomallei. By doing so, we produced a TFD that displayed MIC concentrations lower than ceftazidime, meropenem, and co-trimoxazole against B. thailandensis.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	James Tweddle
Date Deposited:	08 Dec 2022 17:04
Last Modified:	08 Dec 2022 17:04
URI:	https://ueaeprints.uea.ac.uk/id/eprint/89993
DOI:

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