VDEC develops a tool to reduce antimicrobial resistance to tuberculosis
VDEC developed a standardised assay reduce the development of antimicrobial resistance and improve patient treatment for tuberculosis.
Executive summary
The Vaccine Development and Evaluation Centre (VDEC) has developed a standardised assay as a tool to screen compound libraries against Mycobacterium tuberculosis in conjunction with a commonly used chemotherapy drug, to both reduce the development of antimicrobial resistance (AMR) and hopefully improve patient treatment.
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Target
Tuberculosis caused by M. tuberculosis leads to 1.6 million deaths a year. Elevated levels of resistance to drugs makes treatment of tuberculosis particularly difficult and contributes to the growing threat of antimicrobial resistance (AMR). To meet the WHO goal of ending tuberculosis by 2035 we urgently need novel therapies that shorten treatment time and include strategies which target AMR Mycobacterium tuberculosis.
Aims
An important aim for improving tuberculosis treatment is to shorten the period of antibiotic therapy without increasing relapse rates or encouraging the development of antibiotic-resistant strains. Pyrazinamide (PZA) is a key component of front-line chemotherapy against M. tuberculosis and plays an essential role in the shortened 6-month treatment course. Boosting PZA activity could reduce the emergence of resistance, shorten treatment times, and lead to a reduction in the quantity of PZA consumed by patients, thereby reducing the toxic effects.
Issues
In vitro assessments for PZA are often avoided because of the lack of standardisation, which has led to a lack of effective in vitro tools for assessing/enhancing PZA activity.
Options
We have addressed this gap by firstly defining the conditions for PZA assessment in fermenter models that replicate the acidic conditions that PZA is active in (1), and, secondly, by applying this knowledge to the development of a standardised assay to screen for active molecules and perform further characterisation.
VDEC’s unique capability
Through a collaborative project with industrial partners we have screened large compound libraries (defined as having more than 80,000 compounds) to find molecules that enhance the efficacy of PZA, thereby reducing toxicity and extending its life. This approach is being applied by the team for the screening of compound libraries against other AMR pathogens including:
- Pseudomonas aeruginosa
- Neisseria gonorrhoeae
- Mycobacterium abscessus
- carbapenem-resistant
- Enterobacterales
- viral threats such as coronaviruses
- Coalition for Epidemic Preparedness Innovations (CEPI) priority pathogens
We are the only research group in the UK using a combination of fermentation, molecular methods, and bespoke high-throughput screening (HTS) assays for drug discovery and evaluation in pathogenic bacteria.
Details and priorities
The Discovery team at the UK Health Security Agency (UKHSA), Porton Down, focuses on the discovery and development of therapeutics for AMR, by addressing fundamental questions about drug resistance and antigen discovery through to the pre-clinical evaluation of novel and existing antimicrobials, in collaboration with academia, the public sector, and industry worldwide. To achieve our goals, the team has developed novel, disease-relevant, defined, growth models, and rare technologies, which range from fermenter models to rapid, modernised, high throughput assays for determining antimicrobial activity.
Outcome
The team has discovered hits that potentiate PZA and are now characterising them and determining their mode of action against M. tuberculosis.
Future work
The assay method has been accepted for publication (2).
References
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Steven T. Pullan, Jon C. Allnutt, Rebecca Devine, Kim A. Hatch, Rose E. Jeeves, Charlotte L. Hendon-Dunn, Philip D. Marsh, Joanna Bacon. “The effect of growth rate on pyrazinamide activity in Mycobacterium tuberculosis - insights for early bactericidal activity?” (2016) BMC Infectious Diseases 16: 205
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Christopher W. Moon, Eleanor Porges, Stephen C. Taylor, and Joanna Bacon. “A microtitre plate assay at acidic pH to identify potentiators that enhance pyrazinamide activity against Mycobacterium tuberculosis. (chapter) Antibiotic resistance Protocols, 4th Edition (2024) Springer Protocols, Humana Press.