title: A dual-targeting approach to inhibit Brucella abortus replication in human cells.
abstract: 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.
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, United States of America.|Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.
authors: Daniel M
authors: DM
authors: Czyż
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, United States of America.|Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.
authors: Neeta
authors: N
authors: Jain-Gupta
authors: Department of Microbiology, University of Chicago, Chicago, Illinois, United States of America.
authors: Howard A
authors: HA
authors: Shuman
authors: Howard Taylor Ricketts Laboratory, University of Chicago, Argonne National Laboratory, Lemont, Illinois, United States of America.|Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, United States of America.|Department of Microbiology, University of Chicago, Chicago, Illinois, United States of America.
authors: Sean
authors: S
authors: Crosson
mesh_terms: D002003:Brucella abortus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D008856:Microscopy, Fluorescence; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries