Health Science Reviews

by Asande Vilane

Note: this blog is based on a 2018 review by Tiberi et al titled ‘New drugs and perspectives for anti-tuberculosis regimens’. It is third on the reference list and is thus indicated by the [3] in text referencing. Information that has been taken from other sources to provide further background information has been cited accordingly.

Above: the discovery of new anti-TB drugs is necessary to fight the threat of this debilitating disease. Faced with a slowing antibiotic discovery timeline, can scientists innovate new ways of addressing this deadly infection? Image taken from: https://www.technologynetworks.com/drug-discovery/articles/expediting-drug-discovery-using-novel-target-based-approaches-357879

In 2020, 1.5 million people succumbed to tuberculosis (TB)[1]. This debilitating disease, primarily affecting the lungs[2], is commonly treated with a six month regimen consisting of four different drugs, but various factors decrease the efficacy of this approach. In addition to issues with compliance, the treatment is not always well tolerated nor well prescribed, and may have devastating side-effects such as damage to the liver[3]. These issues with treatment adherence, tolerability and sub-optimal drug levels can lead to the development of multi-drug or extremely drug resistant TB (MDR and XDR TB respectively). MDR and XDR TB require more expensive, and increasingly toxic treatments, and have poorer outcomes as compared to drug sensitive TB[3]. Keeping the above in mind, scientists from around the world embarked on a non-systematic literature review to assess progress in the search for new anti-TB treatments – with the intention of assessing and highlighting key advances in the search for new anti-TB treatment approaches.

Discovering and isolating and assessing novel compounds for the treatment of TB is notoriously difficult and time-consuming with a high cost and an even higher rate of failure[3]. This, together with the need of for-profit companies to commercialize drugs for profit has led to research and development in this area slowing down in recent years. To date, only eight new drugs are in the pipeline with two having moved into the latter stages of confirmatory studies. Bearing this in mind, researchers [3] turned their attention to existing drugs used in the treatment of other diseases. This approach is advantageous as these drugs have already been tested and approved for their safety in humans and are manufactured at scale, and thus would be quickly available for treatment use.

They found that the leprosy drug clofazimine as well as the carbapenem class of antibiotics are promising drugs for use against TB[3]. In several studies, clofazimine was shown to be able to kill the TB-causing bacteria in the lungs. These results were further supported by randomized controlled trials (trials which tested the effects of clofazimine vs current interventions in a non-biased manner) as well as a meta-analysis (a systematic analysis of all the research on the topic) which reported an overall success rate of 61%. Additionally, clofazimine’s pharmacokinetic characteristics (the drug’s effect on the body), such as its tissue distribution, intra-cellular distribution and prolonged half-life make it a prime candidate for use as part of second line anti-TB treatment. Despite this, side-effects such as skin discoloration and heart conduction issues may hinder its advance to use for drug-susceptible TB.

Carbapenems (antibiotics typically used to treat a variety of other infections) have also shown promising results when used to treat MDR TB[3]. This has been shown by in-vitro activity, case reports and recently promising results from a phase 2b randomized control early bactericidal activity trial. Together, these results have prompted a whole new look at the management of drug resistant tuberculosis and have inspired new and innovative approaches to drug development in the context of TB.

While TB remains a global threat, there are still some promising leads when it comes to pioneering new approaches to treat this disease. Scientists such as [3] have highlighted that even when the search for new compounds becomes elusive, repurposing existing solutions can still offer some hope – paving the way for new frontiers in our clinical approach to tuberculosis disease.

References

1.         (WHO), W.H.O., Global Tuberculosis Report, W.H.O. (WHO), Editor. 2021.

2.         Pai, M., Behr, M.A., Dowdy, D., Dheda, K., Divangahi, M., Boehme, C.C., Ginsberg, A., Swaminathan, S., Spigelman, M., Getahun, H., Menzies, D., Raviglione, M., Tuberculosis. Nature Reviews: Disease Primers, 2016. 2.

3.         Tiberi, S., Munoz-Torrico, M., Duarte, R., Dalcomo, M., D’Ambrosio, L., Miglioro, G.B., New drugs and perspectives for new anti-tuberculosis regimens. Pulmonology Journal, 2018. 24(2): p. 86-98.