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Discovery of tuberculosis biomarker improves patient management

Researchers have found a new biomarker that can determine the quantity of tuberculosis-causing bacteria in human spit samples in 98% less time than previous methods. This method can improve patient care and reduce the cost and speed of clinical trials improving tuberculosis drug development.

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Tuberculosis (TB) causes over one million deaths annually, and with an increase in anti-bacterial resistance, new drug development is crucial.

In order to test the effectiveness of new TB drugs, medical researchers must assess the number of live Mycobacterium tuberculosis in sputum samples (material coughed up from the patient's lung) throughout treatment. Current tests depend on growing a culture of the bacteria to determine the number of organisms and this can take up to eight weeks. Culture-based methods are prone to error because some of the disease-causing bacteria may be alive, but not able to grow on the artificial medium. This makes new TB drug development extremely expensive and time-consuming.

Professor Stephen Gillespie decided to tackle this problem head on by looking for a biomarker (a naturally occurring characteristic used to identify a particular disease) that would help researchers identify the amount of TB bacteria in patient samples without having to rely on growing cultures. In 2010, he and his team discovered a biomarker for Mycobacterium tuberculosis: the 16SrRNA. This particular rRNA strand works well as a biomarker because it is only found in living cells but does not degrade as quickly as messenger RNA.

Using the biomarker, researchers use PCR to quantify the number of copies of 16s rRNA in less than four hours (in comparison with the three months it takes to grow culture), meaning researchers can evaluate a patient's response to treatment in real time and is being used to study new drugs in clinical trials. In addition, using this biomarker reduces errors because it can detect disease-causing bacteria which are alive but undetectable by culture-based methods.

The recently completed large-scale clinical trial in three African centres: the PANBIOME study, has enabled the group to move forward toward CE marking, the next step to making the test available commercially. At present, the team are working with Life Arc (formerly MRC Technology) and are just at the end of their evaluation stage.

This revolutionary technique is used as an example of methods to modernise microbiology at the Wellcome Trust Advanced Course for Genomics in Clinical Microbiology at the Sanger Institute. The TB MBLA was the subject of a research and development planning meeting at the University where researchers and opinion formers from across the world came together to share results and to plan how to move the TB MBLA into practice. 

The development of this TB biomarker has significantly reduced the time it takes to quantify the number of LIVE Mycobacterium tuberculosis present in samples, which can be used to monitor patients in the clinic or in clinical trials. This reduces the cost for health services, researchers and pharmaceutical companies when making decisions on treatment response.

Impact

  • The detection of the new biomarker has eliminated the need for culture methods, allowing researchers to detect and quantify all TB bacteria in 98% less time.

  • The biomarker method removes the need for larger sample sizes in clinical trials, reducing the expensive costs of TB trials for commercial companies and partnerships.

  • The biomarker method has been rapidly taken up and applied to the design of current trials, such as by international researchers in the PanACEA Consortium’s MAMS-TB phase 2B study of four new regimens.

Thursday 7 June 2018

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Publications

  • Honeyborne I, McHugh TD, Phillips PPJ, et al. "Molecular Bacterial Load Assay, a Culture-Free Biomarker for Rapid and Accurate Quantification of Sputum Mycobacterium tuberculosis Bacillary Load during Treatment". J Clin Microbiol 2011; 49: 3905-11. DOI: 10.1128/JCM.00547-11
  • Gillespie SH, Sabiiti W, Oravcova K.  Mycobacterial Load Assay. Methods Mol Biol. 2017;1616:89-105. doi: 10.1007/978-1-4939-7037-7_5.
  • Phillips PPJ, Gillespie SH, Boeree M, et al. "Innovative Trial Designs Are Practical Solutions for Improving the Treatment of Tuberculosis". J Infect Dis 2012; 205: S250-7. DOI: 10.1093/infdis/jis041
  • Sabiiti W, Mtafya B, Kuchaka D, Azam K, Viegas S, Mdolo A, Farmer EC, Khonga M, Evangelopoulos D, Honeyborne I, Rachow A, Heinrich N, Ntinginya NE, Bhatt N, Davies GR, Jani IV, McHugh TD, Kibiki G, Hoelscher M, Gillespie SH; PANBIOME (Pan-African Biomarker Expansion Programme) consortium. Optimising molecular diagnostic capacity for effective control of tuberculosis in high-burden settings.  Int J Tuberc Lung Dis. 2016 Aug;20(8):1004-9. 

Funding bodies

Contact

Email: proffice@st-andrews.ac.uk
Phone: 01334 46 2108