Thesis

Design & synthesis of antimicrobial minor groove binders

Creator
Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2024
Thesis identifier
  • T17115
Person Identifier (Local)
  • 201969909
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • Antimicrobial resistance is of great concern to public health as the effectiveness of frontline treatments has declined in recent decades. Strathclyde Minor Groove Binders (3.5 Strathclyde Minor Groove Binders (S-MGBs) - Antimicrobials) are a potential novel class of antimicrobial effective against a wide variety of infectious diseases, including drug resistant pathogens. The urgent need for novel antimicrobials, such as MGB-BP3 (Figure 1, 1.1), is illustrated in the introduction to this thesis. MGB-BP3 is active against Gram-positive bacteria at clinically significant concentrations, however, has shown negligible activity against Gram-negative organisms. Structural modifications were made to MGB-BP3 that allowed for conjugation of moieties hypothesised to increase up-take into bacterial cells, particularly Gram-negative bacteria. As well as this, late-stage diversification strategies were developed and employed to produce a library of chemically diverse, broad-spectrum antimicrobials. The conjugates and late-stage diversification analogues were tested in biological assays to measure antimicrobial activity, and by DNA thermal melt analysis to assess DNA binding. The results showed that no S-MGB with significant anti-Gram negative activity was discovered during this research project. However, the synthetic endeavours were successful, and the majority of compounds generated maintained activity against Gram-positive bacteria. Furthermore, multiple analogues possessed significant broad-spectrum activity against other pathogenic organisms, such as parasites and fungi. It was also demonstrated that selected analogues were capable of stabilising genomic DNA, indicating that the mechanism of action of these molecules was unchanged with respect to the parent compound MGB-BP3. [Illustration of compound available to view in thesis]
Advisor / supervisor
  • Tomkinson, Nicholas
  • Suckling, C. J. (Colin J.)
Resource Type
Note
  • Previously held under moratorium from 4th October 2024 until 5th October 2026.
DOI
Alternative Title
  • Design and synthesis of antimicrobial minor groove binders
Embargo Note
  • Access to this thesis is restricted to Strathclyde users only until 4th October 2029.

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