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ACS Infect Dis DOI:10.1021/acsinfecdis.8b00135

High Throughput Screen Identifies Interferon γ-Dependent Inhibitors of Toxoplasma gondii Growth.

Publication TypeJournal Article
Year of Publication2018
AuthorsRadke, JB, Carey, KL, Shaw, S, Metkar, SR, Mulrooney, C, Gale, JP, Bittker, JA, Hilgraf, R, Comer, E, Schreiber, SL, Virgin, HW, Perez, JR, L Sibley, D
JournalACS Infect Dis
Volume4
Issue10
Pages1499-1507
Date Published2018 Oct 12
ISSN2373-8227
Abstract

Toxoplasma gondii is an obligate intracellular parasite capable of causing severe disease due to congenital infection and in patients with compromised immune systems. Control of infection is dependent on a robust Th1 type immune response including production of interferon gamma (IFN-γ), which is essential for control. IFN-γ activates a variety of antimicrobial mechanisms in host cells, which are then able to control intracellular parasites such as T. gondii. Despite the effectiveness of these pathways in controlling acute infection, the immune system is unable to eradicate chronic infections that can persist for life. Similarly, while antibiotic treatment can control acute infection, it is unable to eliminate chronic infection. To identify compounds that would act synergistically with IFN-γ, we performed a high-throughput screen of diverse small molecule libraries to identify inhibitors of T. gondii. We identified a number of compounds that inhibited parasite growth in vitro at low μM concentrations and that demonstrated enhanced potency in the presence of a low level of IFN-γ. A subset of these compounds act by enhancing the recruitment of light chain 3 (LC3) to the parasite-containing vacuole, suggesting they work by an autophagy-related process, while others were independent of this pathway. The pattern of IFN-γ dependence was shared among the majority of analogs from 6 priority scaffolds, and analysis of structure activity relationships for one such class revealed specific stereochemistry associated with this feature. Identification of these IFN-γ-dependent leads may lead to development of improved therapeutics due to their synergistic interactions with immune responses.

DOI10.1021/acsinfecdis.8b00135
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30058798?dopt=Abstract

Alternate JournalACS Infect Dis
PubMed ID30058798
PubMed Central IDPMC6200635
Grant ListR01 AI118426 / AI / NIAID NIH HHS / United States
U19 AI109725 / AI / NIAID NIH HHS / United States