Authors

Discussion

Cutaneous leishmaniasis (CL) is a human disease caused by species of the insect-borne protozoan parasite Leishmania. CL presents with skin lesions, which can produce lifelong scarring or serious complications. While rarely fatal, CL causes a huge global burden of morbidity and social stigma. Its chronic debilitating nature and link to poverty classify CL as a Neglected Tropical Disease. There is no vaccine, and all available drugs are toxic and increasingly ineffective with rising drug resistance. The lack of known therapeutic targets in Leishmania species hinders drug development, so their discovery is of utmost importance.

Our current work examines 17 anti-kinetoplastid compounds identified at GSK via high throughput phenotypic screening and not currently being pursued in any drug discovery effort. These compounds were triaged by GSK according to anti-kinetoplastid activity in Leishmania (L.) donovani (visceral leishmaniasis) or Trypanosoma cruzi (Chagas Disease) (EC₅₀ ≤ 10 μM), availability (≥ 10 mg), chemical druggability and selectivity (Peña et al., 2015). Using a pipeline of cutting-edge ‘omic’ tools and industrial partnerships, which builds on our previous work (Mina et al., 2021), we aim to deconvolve the modes of action of these compounds in L. major and L. mexicana (causative agents of CL), in the hope of discovering novel therapeutic targets.

To date, we have demonstrated high potency of some of these compounds in L. major and/or L. mexicana and for these produced resistant cell lines by in vitro evolution, which are currently under investigation following whole genome sequencing. Following the identification of potential targets further validation will be sought utilising metabolomics, lipidomics and proteomics, alongside genetic validation of targets. Using CRISPR Cas9 technology the proposed target of the recently identified antileishmanial tamoxifen (a antineoplastic drug; Trinconi et al., 2018), inositol phosphorylceramide synthase, was ablated. The data generated phenotyping these mutant strains demonstrated the importance of this approach in target validation.