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

• Published in: Scientific reports 2016-10, Vol.6 (1), p.35835-35835, Article 35835
• Main Authors: Czyż, Daniel M., Jain-Gupta, Neeta, Shuman, Howard A., Crosson, Sean
• Format: Article
• Language: English
• Subjects: 14/63; 49; 49/98; 631/154/1435/2163; 631/326/22/1290; 631/80/304; Bioactive compounds; Brucella abortus - drug effects; Brucella abortus - growth & development; Brucella abortus - physiology; Brucellosis; Cell culture; Cell Line; Chromosomes; Cytotoxicity; DNA Replication - drug effects; Drug development; Genetic recombination; Humanities and Social Sciences; Humans; Intracellular; Lymphocytes B; Macrophages - cytology; Macrophages - drug effects; Macrophages - microbiology; Metabolism; Microbial Sensitivity Tests; Microscopy, Fluorescence; Mitochondria; multidisciplinary; Pathogens; Protein-tyrosine kinase receptors; Pure culture; Replication; Science; Science & Technology - Other Topics; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Zoonoses
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep35835

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.