Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease

This metabolic network-driven approach identified 15 L. major genes as high-priority targets, 8 high-priority synthetic lethal targets, and 254 FDA-approved drugs. Results were compared to previous literature findings and existing high-throughput screens. Halofantrine, an antimalarial agent that was prioritized using MetDP, showed noticeable antileishmanial activity when experimentally evaluated in vitro against L. major promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated in vitro against L. major and four combinations involving the drug disulfiram that showed superadditivity are presented.A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority L. major targets, which are in turn associated with a select number of FDA-approved drugs that are candidate antileishmanials. Additionally, selection of high-priority double-drug combinations might provide for an attractive and alternative avenue for drug discovery against leishmaniasis.Over one billion people are infected by one or more neglected tropical diseases (NTDs) [1,2]. These diseases comprise a group of parasitic and bacterial infections that affect some of the poorest and most marginalized populations around the world, many who live on less than 1.25 USD a day [2]. Leishmaniasis is one such NTD that is endemic in 88 countries with a total of 350 million people at risk. The disease is associated with a global prevalence of 12 million cases, a yearly incidence of 1.5 to 2 million cases, and an annual mortality rate of over 59,000 deaths [3]. Caused by Leishmania species, the disease can manifest itself in varying clinical pathologies including visceral, cutaneous or mucocutaneous forms [3,4]. These parasites transition through different morphological stages - from flagell