Tuberculosis (TB) is an infectious disease that affects over 10 million people worldwide, of which 10% die if the disease is untreated. Globally it is one of the top 10 diseases that causes death, and over 95% of these deaths occur in low- and middle-income countries. Ending the TB epidemic by 2030 is one of the health targets of the United Nations Sustainable Development Goals, but multidrug-resistant TB (MDR-TB) is a continuing public health crisis and a health security threat.
Eradication of TB is impeded by the need for long complex treatment – six months with four drugs – for durable cure. Furthermore, this need for long treatment could be the catalyst for the development of antibiotic-tolerant TB. Researchers in the Department of Medicine have found that the actively-growing bacteria become antibiotic-tolerant upon entry into host macrophages (part of our immune system, and the bacteria’s site of growth) by inducing bacterial efflux pumps. With this knowledge, the researchers are testing the therapeutic value of a several drugs that are known to inhibit these efflux pumps and are already approved for other purposes. For example, a clinical trial with verapamil (commonly used as an antiarrhythmic) as a treatment-shortening agent has been approved and funded by the Government of India and is entering Phase 2. Linked to this trial, studies to better understand bacterial efflux pump-mediated drug tolerance mechanisms are in progress through a multi-investigator collaborative grant from the British MRC and the Indian Department of Biotechnology.
Other clinical trials are also underway for studies on meningitis TB, the most severe and lethal form of this disease. In this study, Professor Ramakrishnan and colleagues found that TB susceptibility is heightened in conditions of inadequate or excessive inflammation, and is regulated by the balanced production of steroid called eicosanoids. The balance of these steroids is maintained by an enzyme that is referred to as leukotriene A4 hydrolase (LTA4H), and it is variants of this enzyme that control the severity of TB meningitis. Ramakrishnan and colleagues from the Oxford University Wellcome Trust Research Unit (OUCRU) in Vietnam have found that because of this variation in the enzyme, the standard therapy for meningitis TB is only effective in patients with a high inflammatory state, while patients with the low inflammatory state patients may be harmed by it.
Based on this finding, the OUCRU investigators have begun a randomised clinical trial where patients are genotyped and those with the low-LTA4H genotype are given steroid treatment or placebo. If the previous findings are confirmed, then in the future steroid treatment will be restricted to the excessive inflammation subset, improving the outcome of both groups. To address this, in the meantime, the zebrafish is being used to reveal mechanistic details of the LTA4H-mediated low and high inflammatory states. New targets for treatments are being revealed and drugs that have already been approved for other purposes have been identified. The use of personalised genomics will have consequences for guiding clinical treatments, where patients from the two LTA4H genotypes will be treated with different therapies.
Professor Lalita Ramakrishnan