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Effect of antimicrobial materials on the development of antimicrobial resistance among ESKAPE pathogens

Primary Supervisor: Dr Felicity de Cogan, Institute of Microbiology and Infection

Secondary supervisor: Jack Bryant

PhD project title: Effect of antimicrobial materials on the development of antimicrobial resistance among ESKAPE pathogens

University of Registration: University of Birmingham

Project outline:

The increase in antimicrobial resistance (AMR) is a recognised global problem. Current forecasts project that by 2050, it will have led to 10 million preventable deaths, and cost the global economy in excess of £66 trillion. Research and development across different sectors will be key in tackling this problem. We have developed a novel antimicrobial surface which incorporates biocides onto surfaces, is very durable and can last for years. We have demonstrated that the surfaces are effective in killing bacteria, fungi and viruses (including SARS-CoV-2) in seconds. It is considerably faster than any other commercial technology and is resistant to abrasion and common cleaning practices. Our initial studies have also demonstrated that when surfaces incorporate biocides such as chlorhexidine digluconate they are as effective at killing chlorhexidine resistant bacteria as they are at killing naïve bacteria. The technology has been shown to be efficacious in both lab-based and “real world” studies, therefore proving to be highly effective at decreasing the spread of bacteria.

Despite the extremely promising progress made so far with this technology, the widespread use of biocides raises concerns for the potential of antimicrobial resistance and further work is required. The aim of this project would be to investigate the mechanism of action of chlorhexidine and the mechanism by which surfaces inhibit bacterial survival. We will also investigate whether this differs from the effect of the biocide in liquid culture. Depending on progress, the Ph.D. candidate can choose to target the following research objectives:

Objective 1: Compare the mechanisms by which the key ESKAPE pathogens develop resistance to chlorhexidine in either liquid medium or attached to surfaces.

The project will review and optimise the parameters used to generate the surfaces in order to determine the effect on bacteria survival. We will seek to explore this approach in real world settings by taking part in long running studies with industrial collaborators. The project will then use lab-based evolution and next-generation sequencing to compare the mechanisms by which the key ESKAPE pathogens develop resistance to chlorhexidine in either liquid medium or attached to our novel surface technology.

Training: Surface coupling, microscopy, culture of several bacterial species, lab-based evolution, next-generation sequencing.

Objective 2: Characterise the gene networks that become essential for bacterial survival in the presence of chlorhexidine.

We will use high-throughput genetics approaches, such as Transposon Directed Insertion-site Sequencing to characterise the gene networks that become essential for bacterial survival in the presence of sub-inhibitory concentrations of chlorhexidine. These gene “hits” will be validated and investigated further using a range of biochemistry and molecular microbiology approaches. Together, the results of Objective 1 and 2 will define the mechanism of action for chlorhexidine against gram-negative pathogens, which is an existing gap in the literature. These aims will also establish whether mechanisms of resistance to chlorhexidine in liquid media also provide resistance to antimicrobial surfaces.

Training: High-throughput genetics (TraDIS), data analysis, biochemistry.

Objective 3: Screen an existing bank of environmental/clinical isolates for resistance to chlorhexidine.

While the first two objectives will address lab-based evolution of resistance within closed genetic systems, the final objective will aim to characterise mechanisms of resistance arising within the environment. We will use chemical genomics and robotic handling systems to screen an existing bank of environmental/clinical isolates for resistance to chlorhexidine in liquid medium and characterise these mechanisms of resistance by genome sequencing. We will then identify whether any of these strains are capable of survival on antimicrobial surfaces and recapitulate the resistance mechanisms within a naive background. This will allow us to establish whether any of the mechanisms of resistance identified in environmental isolates will facilitate growth on antimicrobial surfaces.

Training: Experience of work with a range of microorganisms, robotic handling systems (Manuel Banzhaf – UoB), high-throughput screening (Manuel Banzhaf – UoB); genome manipulation.

The technology in development has widespread use in many areas, including healthcare where it could prevent the spread of hospital acquired infection, but also in agriculture. It is generally recognised that overuse of antibiotics in agriculture is a major contributor to the evolution and spread of AMR. While legislation is beginning to restrict some of this overuse, there are still major concerns about misuse and high levels of antibiotics in farm run-off, which can select for resistant organisms. This project therefore address BBSRC strategic research priorities of combatting antimicrobial resistance, and technology development for the biosciences.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Animal Health and Welfare & Understanding the Rules of Life:Microbiology

Techniques that will be undertaken during the project:

  • Surface coupling and surface analysis
  • Bacterial culture
  • Data analysis
  • Next-generation sequencing
  • High-throughput genetics: Transposon-directed insertion site sequencing (TraDIS)
  • Chemical genomics
  • Robotic handling
  • Molecular microbiology: Cloning, DNA handling, protein purification, western blotting etc.
  • Microscopy/Fluorescence microscopy
  • Bioinformatics

Contact: Dr Felicity de Cogan, University of Birmingham