Selective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome.

TitleSelective Phenylimidazole-Based Inhibitors of the Mycobacterium tuberculosis Proteasome.
Publication TypeJournal Article
Year of Publication2019
AuthorsZhan W, Hsu H-C, Morgan T, Ouellette T, Burns-Huang K, Hara R, Wright AG, Imaeda T, Okamoto R, Sato K, Michino M, Ramjee M, Aso K, Meinke PT, Foley M, Nathan CF, Li H, Lin G
JournalJ Med Chem
Volume62
Issue20
Pagination9246-9253
Date Published2019 10 24
ISSN1520-4804
KeywordsImidazoles, Microbial Sensitivity Tests, Mycobacterium tuberculosis, Proteasome Inhibitors, Reactive Nitrogen Species, Structure-Activity Relationship
Abstract

Proteasomes of pathogenic microbes have become attractive targets for anti-infectives. Coevolving with its human host, Mycobacterium tuberculosis (Mtb) has developed mechanisms to resist host-imposed nitrosative and oxidative stresses. Genetic deletion or pharmacological inhibition of the Mtb proteasome (Mtb20S) renders nonreplicating Mtb susceptible to reactive nitrogen species in vitro and unable to survive in the lungs of mice, validating the Mtb proteasome as a promising target for anti-Mtb agents. Using a structure-guided and flow chemistry-enabled study of structure-activity relationships, we developed phenylimidazole-based peptidomimetics that are highly potent for Mtb20S. X-ray structures of selected compounds with Mtb20S shed light on their selectivity for mycobacterial over human proteasomes.

DOI10.1021/acs.jmedchem.9b01187
Alternate JournalJ Med Chem
PubMed ID31560200
PubMed Central IDPMC7091493
Grant ListR01 AI070285 / AI / NIAID NIH HHS / United States
R21 AI101393 / AI / NIAID NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States

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