Tag Archives: Tuberculosis

A Novel Drug for Tuberculosis

Once rampant across the globe Tuberculosis has been brought under control, first by improved hygiene standards, and then antibiotic drugs, such as isoniazid and rifampicin, developed in the 1950s and 1960s. However, it remains one of the top 10 causes of death across the world, infecting 10.4 million people and killing 1.8 million in 2015, the vast majority (95%) in low- and middle-income countries.[1] Further, there has been a rise of TB strains that are resistant to antibiotics – around 480,000 people developed multi-drug resistant TB (MDR-TB) in 2015.[1] Of these, only 52% were successfully treated by second-line treatment options, such as extensive chemotherapy. More worryingly, there has been a rise in cases developing extensive drug resistance (XDR-TB), which has very limited treatment options. One of the United Nation’s Sustainable Development Goals is to end the TB epidemic by 2030, but to do this new antibiotics are needed to which no resistance has developed.

University of Warwick researcher Gregory Challis, together with Eshwar Mahenthiralingam and colleagues, recently discovered a promising candidate – gladiolin. [2] Bacteria belonging to the genus Burkholderia are able to thrive in a diverse range of environments thanks to their ability to produce potent antibiotics to remove any competition. Researchers were able to isolate gladiolin by screening one such strain, B. gladioli, that was taken from a child with cystic fibrosis. Gladiolin works by inhibiting RNA polymerase (a validated drug target in TB), has significantly improved chemical stability compared to structurally similar antibiotics, and has low cytotoxicity in mammals. Further research found that while gladiolin was less effective (compared to isoniazid and rifampicin) against strains of TB with no resistance, it had good activity against several strains of TB that were resistant to isoniazid and rifampicin. It is hoped that gladiolin will be the starting point for developing new drugs that can tackle MDR-TB and XDR-TB.

— Peter Chilton, Research Fellow

References:

  1. World Health Organization. Tuberculosis Fact Sheet. 2017.
  2. Song L, Jenner M, Masschelein J, et al. Discovery and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity against Mycobacterium tuberculosis. J Am Chem Soc. 2017; 139(23): 7974-81.
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Boosting the Body’s Natural Immunity

The Professor of Microbiology at St Mary’s Hospital in the years leading up to World War 2 was Sir Almroth Wright. He thought that the quest for antimicrobial drugs was doomed and instead promoted the search for methods to boost the natural immunity of the body. Unfortunately he worked in the same department as Alexander Fleming, so after the discovery of penicillin the students nicknamed him Sir Almost Right! But was he only almost right? Time would seem to vindicate his approach, at least with respect to tuberculosis (TB) according to a recent article in Nature Reviews.[1] TB organisms are developing resistance, TB drugs may interact with anti-HIV treatment (Immune Reconstitution Inflammatory Syndrome), and prolonged maintenance of therapy is required. Many treatments to fight the disease by boosting the body’s immune response are now in trials. These include cell therapies, such as mesenchymal stem cell treatment, and repurposed drugs, such as vitamin D (that induces release of anti-microbial peptides) and the anti-cancer kinase inhibitor imatinib, and therapeutic vaccines designed specifically to augment immunity.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Zumla A, Chakaya J, Hoelscher M, et al. Towards host-directed therapies for tuberculosis. Nat Rev Drug Discov. 2015; 14(8):511-2.

Vaccinations and Anti-retroviral Therapy

When I was at medical school, we were told that BCG vaccination reduced the risk of serious tuberculosis (TB) by a greater proportion than the reduction in infection of a milder or innocuous nature. However, until recently, it has been difficult to distinguish between infection and the effects of an earlier infection, previous BCG vaccination, or non-TB mycobacterial infection. A recent paper, using newer tests that can distinguish between these events, has confirmed what my teachers said at medical school – BCG protects against infection and protects even more against active disease.[1]

Meanwhile, a cluster RCT from CLAHRC Africa collaborators shows that initiating anti-retroviral therapy at home, rather than in hospital, increases uptake of therapy nearly three-fold. This practice was ‘dominant’, promising greater effectiveness at lower upfront and net costs.[2] A lot of research may be a waste of money, but not this study.

–Richard Lilford, CLAHRC WM Director

References:

  1. Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, Snell L, Mangtani P, Adetifa I, Lalvani A, Abubakar I. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ. 2014; 349: g4643.
  2. MacPherson P, Lalloo DG, Webb EL, Maheswaran H, Choko AT, Makombe SD, Butterworth AE, van Oosterhout JJ, Desmond N, Thindwa D, Squire SB, Hayes RJ, Corbett EL. Effect of Optional Home Initiation of HIV Care Following HIV Self-testing on Antiretroviral Therapy Initiation Among Adults in Malawi. A Randomized Clinical Trial. JAMA. 2014; 312(4): 372-9.