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In this article, with the application of selection criteria for both <jats:italic>Leishmania major<\/jats:italic> targets (e.g. <jats:italic>in silico<\/jats:italic> gene lethality) and drugs (e.g. toxicity), a method (MetDP) to rationally focus on a subset of low-toxic Food and Drug Administration (FDA)-approved drugs is introduced.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>This metabolic network-driven approach identified 15 <jats:italic>L. major<\/jats:italic> 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 <jats:italic>in vitro<\/jats:italic> against <jats:italic>L. major<\/jats:italic> promastigotes. Furthermore, synthetic lethality predictions also aided in the prediction of superadditive drug combinations. For proof-of-concept, double-drug combinations were evaluated <jats:italic>in vitro<\/jats:italic> against <jats:italic>L. major<\/jats:italic> and four combinations involving the drug disulfiram that showed superadditivity are presented.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A direct metabolic network-driven method that incorporates single gene essentiality and synthetic lethality predictions is proposed that generates a set of high-priority <jats:italic>L. major<\/jats:italic> 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-6-27","type":"journal-article","created":{"date-parts":[[2012,4,27]],"date-time":"2012-04-27T20:14:23Z","timestamp":1335557663000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Metabolic network analysis predicts efficacy of FDA-approved drugs targeting the causative agent of a neglected tropical disease"],"prefix":"10.1186","volume":"6","author":[{"given":"Arvind K","family":"Chavali","sequence":"first","affiliation":[]},{"given":"Anna S","family":"Blazier","sequence":"additional","affiliation":[]},{"given":"Jose L","family":"Tlaxca","sequence":"additional","affiliation":[]},{"given":"Paul A","family":"Jensen","sequence":"additional","affiliation":[]},{"given":"Richard D","family":"Pearson","sequence":"additional","affiliation":[]},{"given":"Jason A","family":"Papin","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2012,4,27]]},"reference":[{"issue":"9674","key":"867_CR1","doi-asserted-by":"publisher","first-page":"1570","DOI":"10.1016\/S0140-6736(09)60233-6","volume":"373","author":"PJ Hotez","year":"2009","unstructured":"Hotez PJ, Fenwick A, Savioli L, Molyneux DH: Rescuing the bottom billion through control of neglected tropical diseases. 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