Chagas disease drug-development is being limited by gaps in our knowledge of parasite biology
The latest Paper of the Month from Parasitology is by Amanda F. Francisco, Shiromani Jayawardhana, Michael D. Lewis, Martin C. Taylor, and John M. Kelly.
The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. The only available therapeutic treatments are the nitroheterocyclic drugs benznidazole and nifurtimox. However, both can have debilitating side effects, and treatment failures are widely reported. The search for new drugs against Chagas disease is an international effort that involves both the academic and commercial sectors, together with not-for-profit drug development consortia. Until recently, the anti-fungal agent posaconazole was widely perceived as the leading candidate to be the “next-generation” Chagas disease drug. Posaconazole had many attributes to underpin this community-wide enthusiasm. It is an inhibitor of ergosterol biosynthesis, a pathway that is absent from mammals, it is already licenced for use in humans and is well tolerated, it has an EC50 value in the low nanomolar range, and preliminary experiments in animal models showed great promise. Consequently, there was major disappointment when posaconazole failed in clinical trial (1).
In 2014, the Drugs for Neglected Diseases initiative (DNDi) asked my lab to re-visit posaconazole efficacy, using the highly sensitive bioluminescence imaging model that we had developed to monitor experimental infections in mice (2). These studies did indeed show posaconazole to be highly effective at reducing parasite burden, in both the acute and chronic stages of the infection. However, in the large majority of cases, it was not possible to eliminate the parasite, and the infection relapsed following the cessation of treatment (3). Parallel studies by others produced similar results (4).
These unfavourable outcomes posed a number of questions that highlighted the limitations of our current understanding of basic parasite biology and host:pathogen interactions. For example, is there a biochemically quiescent or dormant stage of the parasite that is refractory to metabolic inhibitors? Do parasites survive in specific organ/tissue site(s) that are less accessible to the drug? Are all parasite life-cycle stages equally susceptible to trypanocidal agents? It was apparent that many aspects of pathogenesis remain to be resolved, and that these gaps in our fundamental knowledge of Chagas disease threaten to undermine progress in drug development. In our review for Parasitology, we identified four major research questions: (i) Does parasite diversity impact on drug efficacy? (ii) Do drugs have to target all mammalian life-cycle stages? (iii) Does parasite tropism have implications for therapeutic outcomes? (iv) Does drug treatment actually alleviate the development of chronic disease pathology? Addressing these questions represents a significant challenge, both to ourselves and others. The goal of providing a more informed framework for drug discovery will be a community-wide effort that will require the development and application of technically innovative approaches.
(1) Molina, I. et al. (2014) New England Journal of Medicine 370, 1899-1908.
(2) Lewis, M.D. et al. (2014) Cellular Microbiology 16, 1285-1300.
(3) Francisco, A.F. et al. (2015) Antimicrobial. Agents and Chemotherapy 59, 4653-4661.
(4) Khare, S. et al. (2015) Antimicrobial Agents and Chemotherapy 59, 6385–6394.
Read the full article ‘Biological factors that impinge on Chagas disease drug development‘ in full for free until 31st December 2017.