A dual-targeting approach to inhibit Brucella abortus replication in human cells

Czyż, Daniel M.; Jain-Gupta, Neeta; Shuman, Howard A.; Crosson, Sean

doi:10.1038/srep35835

Title: A dual-targeting approach to inhibit Brucella abortus replication in human cells

Journal Article · Fri Oct 21 00:00:00 EDT 2016 · Scientific Reports

DOI:https://doi.org/10.1038/srep35835· OSTI ID:1624868

Czyż, Daniel M. ^[1]; Jain-Gupta, Neeta ^[1]; Shuman, Howard A. ^[2]; Crosson, Sean ^[3]

Virginia Maryland College of Veterinary Medicine, Blacksburg, VA (United States). Dept. of Biomedical Sciences and Pathobiology; Argonne National Lab (ANL), Lemont, Illinois, (United States). Howard Taylor Ricketts Laboratory, University of Chicago; Univ. of Chicago, Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology
Virginia Maryland College of Veterinary Medicine, Blacksburg, VA (United States). Dept. of Biomedical Sciences and Pathobiology; Univ. of Chicago, Chicago, IL (United States). Dept. of Microbiology
Virginia Maryland College of Veterinary Medicine, Blacksburg, VA (United States). Dept. of Biomedical Sciences and Pathobiology; Argonne National Lab (ANL), Lemont, Illinois, (United States). Howard Taylor Ricketts Laboratory, University of Chicago; Univ. of Chicago, Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology; Univ. of Chicago, Chicago, IL (United States). Dept. of Microbiology

Brucella abortus is an intracellular bacterial pathogen and an etiological agent of the zoonotic disease known as brucellosis. 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 in vitro metabolism and intracellular replication to screen a library of 480 known bioactive compounds for novel B. abortus anti-infectives. Eighteen non-cytotoxic compounds specifically inhibited B. abortus replication in the intracellular niche, which suggests these molecules function by targeting host cell processes. Twenty-six compounds inhibited B. abortus metabolism in axenic culture, thirteen of which are non-cytotoxic to human host cells and attenuate B. abortus replication in the intracellular niche. The most potent non-cytotoxic inhibitors of intracellular replication reduce B. abortus 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 B. abortus replication in the intracellular niche suggests “dual-target” compounds that coordinately perturb host and pathogen are promising candidates for development of improved therapeutics for intracellular infections.

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Research Organization:: Argonne National Lab (ANL), Lemont, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Chicago Biomedical Consortium; Searle Funds at the Chicago Community Trust

Grant/Contract Number:: AC02-06CH11357; 1U19AI107792; 1R01AI107159

OSTI ID:: 1624868

Journal Information:: Scientific Reports, Vol. 6, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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