Antimicrobial Resistance and Infection

Antimicrobials have revolutionised the treatment of infectious diseases but addressing antimicrobial resistance (AMR) is paramount to protect these gains and maintain antibiotics as enablers for modern medicine. AMR-related deaths may exceed those from cancer by 2050 with associated costs of $100 trillion – more than the sum of all global economies combined. Our vision to address AMR uses a multipronged strategic approach focussing on

1. Driving down infections; using smarter diagnosis; and protecting existing antibiotics

2. Creating new, more targeted treatments.

The BRC will provide a step-change to AMR research at Leeds, expanding our NIHR-funded capital infrastructure by investing in personnel and expertise. We will take a bench-to-bedside approach that tackles AMR at multiple points within our fundamental and translational research workstreams:

WS1 Prof Mark Wilcox; Targeted AMR Solutions

WS1a. Developing precision diagnostics: the COVID-19 pandemic has highlighted the importance of rapid, accurate diagnosis of infection. AMR is the next pandemic. We will leverage our experience at the forefront of the COVID-19 diagnostic response to meet this need.

Grand challenge: to optimise diagnosis of life-threatening AMR infections, transforming patient care with targeted antimicrobial treatment, driving down the collateral damage caused by healthcare associated infections and spread of multi-resistant organisms. We will improve patient outcomes by reducing inappropriate prescribing, infection and AMR rates and disparities across healthcare settings, by developing the right tests and using them in the right place, at the right time. We will establish a Testing and Evaluation Centre for new AMR/Infection diagnostic tests (AMR-TEC), building on the national COVID testing rapid validation/verification infrastructure we have created here at Leeds and positioned to attract both grant and industrial funding.

The BRC investment will provide infrastructure to support a wider range of AMR/Infection diagnostic projects, such as:

  • Repurposing and optimising existing infection diagnostic tests through clinical trials, such as repurposing existing diagnostic tests to predict recurrent CDI and evaluating high throughput AMR urinary tract infection diagnostics. This will reduce costs, improve diagnostic accuracy and facilitate targeted treatments for better patient outcomes.
  • Tackling disparities in diagnosis/treatment access. We will evaluate disparities in access to diagnostic testing and treatments for infections between community and hospital patients. This has the potential to improve access for patients to diagnostics and treatments across both primary and secondary care.

WS1b. Optimising Antimicrobial Stewardship (AMS): optimal AMS strategies are underpinned by robust evidence. This is commonly lacking, making some current approaches sub-optimal and/or poorly implemented. Grand Challenge: generate robust evidence to validate current AMS strategies and design innovative interventions, for patient and public health benefit. We will develop, evaluate and refine new and existing approaches to antimicrobial stewardship, using big data, working with UKHSA, NHS Trusts and commercial partners such as TPP, provider of SystemOne (used by 2600 UK GP practices).

Both WS1a and b will draw on statistical provision through the Theme to design and analyse validation, observational and interventional studies, and health economic expertise to evaluate the potential benefits/impacts in healthcare settings. For example, oral/iv switch: Switching from IV to oral antimicrobials is a fundamental part of hospital practice, allowing patients to recuperate at home. It is hypothesised that this reduces AMR development, but evidence is lacking. We will explore the basis for this in a systematic review, to inform an evidence-based AMS intervention that will be tested in a clinical trial.

WS2; Prof Alex O’Neill: Translational Pipeline for antimicrobial solutions.

While levels of resistance in micro-organisms are increasing, the development of new antimicrobials is not. If we are to avoid a return to the pre-antibiotic era, rapid development of new antimicrobials is paramount. We will harness our existing expertise in AMR, gut models and microbiome, to develop an innovative development pipeline for antimicrobial solutions. Grand challenge: springboard from our existing, highly sought-after pipeline to a rapid, high throughput system, to streamline and expedite translation of new drugs from early stage development to NHS care.

WS2a Pre-clinical Studies:
We will increase treatment options by streamlining and expediting the translation of antimicrobial and non-antimicrobial drug discovery with industry involvement, and re-examining and re-purposing existing antimicrobials. Our highly sought-after human gut models will be used to generate data on dosing regimens for both novel and existing antimicrobials, or biotherapeutics. We will augment our previous gut model data generation with pharmacological, genomic and proteomic data via infrastructure provided by our £2.1M NIHR AMR capital grant.

By combining the infrastructure support of this bid with the capital equipment secured in our NIHR AMR capital equipment award, we will have the power to conduct large-scale molecular AMR studies on clinical isolates to generate robust data sets.

For example, current routine diagnostic laboratory tests may not detect all forms of AMR. We will perform comprehensive analysis to detect hidden resistance on isolates recovered from patients failing treatment, to develop new diagnostic tests to be evaluated in WS1.

WS2b Innovative, high throughput mini-models for the Antimicrobial development pipeline:
We will further develop our existing, highly sought-after gut models by developing the Leeds mini-models, increasing throughput/capacity for initial screening of novel antimicrobial/non-antimicrobial compounds for their propensity to affect (deleteriously or advantageously) the gut microbiome and AMR bacteria. The initial investment in consumables as part of the pipeline development will be returned in the later years of the BRC, when we anticipate high demand for the mini-models from industry, providing funding from both research councils and commercial sources, so becoming self-sustaining.

To expedite the translation of both antimicrobial and non-antimicrobial AMR solutions into clinical practice, we will synergise fundamental academic science, PPIE contributors, industrial knowhow, and clinical expertise. The workstream will support a dynamic group interfacing disciplines to feedback and co-build pre-clinical and clinical studies. We will feedback to industry and grow our impact in this sector by creating an Industry Incubator meeting each year showcasing our research and facilities and attracting further investment.

We have a significant track record of supporting both clinical and non-clinical PhD students through to successful completion, including providing support for students with disabilities to compete for funding and complete PhDs. Many of our students have gone on to join the team in post-doctoral posts, with the rest successful in securing posts elsewhere in academia and industry.