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Brucellosis can be challenging to treat with conventional antibiotic therapies and, in some cases, may develop into a debilitating and life-threatening chronic illness. We used multiple independent assays of<jats:italic>in vitro<\/jats:italic>metabolism and intracellular replication to screen a library of 480 known bioactive compounds for novel<jats:italic>B. abortus<\/jats:italic>anti-infectives. Eighteen non-cytotoxic compounds specifically inhibited<jats:italic>B. abortus<\/jats:italic>replication in the intracellular niche, which suggests these molecules function by targeting host cell processes. Twenty-six compounds inhibited<jats:italic>B. abortus<\/jats:italic>metabolism in axenic culture, thirteen of which are non-cytotoxic to human host cells and attenuate<jats:italic>B. abortus<\/jats:italic>replication in the intracellular niche. The most potent non-cytotoxic inhibitors of intracellular replication reduce<jats:italic>B. abortus<\/jats:italic>metabolism in axenic culture and perturb features of mammalian cellular biology including mitochondrial function and receptor tyrosine kinase signaling. The efficacy of these molecules as inhibitors of<jats:italic>B. abortus<\/jats:italic>replication in the intracellular niche suggests \u201cdual-target\u201d compounds that coordinately perturb host and pathogen are promising candidates for development of improved therapeutics for intracellular infections.<\/jats:p>","DOI":"10.1038\/srep35835","type":"journal-article","created":{"date-parts":[[2016,10,21]],"date-time":"2016-10-21T09:39:32Z","timestamp":1477042772000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["A dual-targeting approach to inhibit Brucella abortus replication in human cells"],"prefix":"10.1038","volume":"6","author":[{"given":"Daniel M.","family":"Czy\u017c","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neeta","family":"Jain-Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard A.","family":"Shuman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Crosson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,10,21]]},"reference":[{"key":"BFsrep35835_CR1","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/S1473-3099(06)70382-6","volume":"6","author":"G Pappas","year":"2006","unstructured":"Pappas, G., Papadimitriou, P., Akritidis, N., Christou, L. & Tsianos, E. 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