An evaluation of antimicrobial compounds for clinical and diagnostic use with particular emphasis on phosphonopeptides

  • Emma Marrs

Abstract

Infectious disease has been the major cause of morbidity and mortality throughout the ages. Since being marketed in the early 20th century, antimicrobial agents have not only been keeping such diseases at bay but have had a dramatic impact on the development of modern medical practices and subsequently on life expectancy. Given this, anything that affects their viability would be disastrous.
Resistance to these wonder drugs is now a global public health issue, which threatens to push us into a post-antibiotic era. Although there are a number of strategies being implemented to protect the agents currently on the market and improve prescribing protocols, there is a need for novel agents that is presently not being met. The antimicrobial pipeline is now becoming the focus of Research and Development departments in many pharmaceutical companies as well as academia. The approaches undertaken involve the re-examination of previously abandoned agents, synthesis of new agents and discovery of natural products from previously unexplored niches.
As microbiological culture methods are crucial in not only the identification of infectious disease vectors but determining appropriate antimicrobial treatment, a high degree of accuracy and a rapid turnaround time are crucial. Decreasing these turnaround times would also aid in abating the development and spread of resistance.
The aim of this project was to investigate the antimicrobial efficacy of a number of putative antimicrobial compounds originating from various sources, including those of the phosphonopeptide class. The compounds were screened against panels of well defined control strains, as well as resistant isolates and where appropriate alongside other conventional agents to determine the presence of synergy.
Good activity was observed for phosphonopeptides against both Gram-positives and Gram-negatives, including resistant isolates. Alafosfalin and a novel derivative had notable activity against resistant Enterobacteriaceae, especially Escherichia coli. Synergistic interaction was found when alafosfalin was combined with cell wall active agents. Majority of the other substrates investigated had an anti-Gram-positive spectrum.
A novel substrate, β-chloro-L-alafosfalin, was incorporated into a chromogenic medium selective for Salmonella species, with the aim of improving isolation following direct culture from faecal samples. The medium was evaluated alongside three commercially available media and another prototype medium. The β-chloro-L-alafosfalin chromogenic medium afforded a higher isolation rate of Salmonella spp. on direct culture and had the highest sensitivity.
Date of Award13 Jun 2016
Original languageEnglish
Awarding Institution
  • Northumbria University
SupervisorJohn D. Perry (Supervisor), Amanda Jones (Supervisor) & Stephen Cummings (Supervisor)

Keywords

  • antimicrobial resistance
  • carbapenemase-producing Enterobacterales (previously Enterobacteriaceae)
  • cell wall inhibitors
  • natural products and antimicrobial discovery
  • revisiting old/abandoned antibiotics

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