Abstract
A lack of viable hits, increasing resistance, and limited knowledge on mode of action is hindering drug discovery for many diseases. To optimize prioritization and accelerate the discovery process, a strategy to cluster compounds based on more than chemical structure is required. We show the power of metabolomics in comparing effects on metabolism of 28 different candidate treatments for Leishmaniasis (25 from the GSK Leishmania box, two analogues of Leishmania box series, and amphotericin B as a gold standard treatment), tested in the axenic amastigote form of Leishmania donovani. Capillary electrophoresis-mass spectrometry was applied to identify the metabolic profile of Leishmania donovani, and principal components analysis was used to cluster compounds on potential mode of action, offering a medium throughput screening approach in drug selection/prioritization. The comprehensive and sensitive nature of the data has also made detailed effects of each compound obtainable, providing a resource to assist in further mechanistic studies and prioritization of these compounds for the development of new antileishmanial drugs.
Highlights
D ue to a lack of viable hits or increasing resistance to currently available treatments, the bottleneck in research toward new therapies for many different diseases is a growing concern
The challenge has been addressed previously, mainly for gas chromatography−mass spectrometry (GC-MS) and liquid chromatography−mass spectrometry (LC-MS) data,[21,22] to our knowledge it has not been addressed for CE-MS based metabolomics
We have shown that compounds with different chemical structure and physicochemical properties can disturb the same metabolic pathways, while others with more similar structures can have different downstream effects
Summary
D ue to a lack of viable hits or increasing resistance to currently available treatments, the bottleneck in research toward new therapies for many different diseases is a growing concern. Limited knowledge on the mode of action (MoA) or polypharmacological effects of existing treatments could be hindering the discovery of new compounds. For diseases where drug repurposing is a popular approach, e.g., for neglected tropical diseases, MoA studies are important since compounds were not originally designed to target the new disease type. Leishmania donovani provokes one of the most severe forms, that is, visceral leishmaniasis,[2] and existing therapeutic options for this are limited.[3] From a recent screening of 1.8 million compounds against the three kinetoplastid parasites most relevant to human disease (Leishmania donovani, Trypanosoma brucei, and Trypanosoma cruzi), 192 noncytotoxic active hits against Leishmania donovani were selected to be included in the socalled Leishmania box.[2] While some general hypotheses were generated relating to compound structure, suggesting that many of them could target kinases, proteases, cytochromes, and host−pathogen interactions, the MoA of each is still unknown. The metabolomics approach to study the MoA of compounds for drug discovery purposes has been successfully applied in many fields. See Vincent and Barrett[5] for parasitology, Armitage and Southam[6] for oncology, Rankin et al.[7] for cardiology, Adamski[8] for diabetes, Atzori et al.[9] for perinatology, Gennari et al.[10] for osteoporosis drug discovery, dos Santos et al.[11] for antibacterial MoA of plant derived products, Mikami et al.[12] for updates specific to MSbased metabolomics, and Hoerr et al.[13] for updates specific to NMR-based metabolomics
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