Targeting Mycobacterium tuberculosis Persistence through Inhibition of the Trehalose Catalytic Shift

Kalera, Karishma; Liu, Rachel; Lim, Juhyeon; Pathirage, Rasangi; Swanson, Daniel H.; Johnson, Ulysses G.; Stothard, Alicyn I.; Lee, Jae Jin; Poston, Anne W.; Woodruff, Peter J.; Ronning, Donald R.; Eoh, Hyungjin; Swarts, Benjamin M.

doi:10.1021/acsinfecdis.4c00138

Targeting Mycobacterium tuberculosis Persistence through Inhibition of the Trehalose Catalytic Shift

Journal Article · Thu Mar 14 00:00:00 EDT 2024 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.4c00138· OSTI ID:2470179

Kalera, Karishma ^[1]; Liu, Rachel ^[2]; Lim, Juhyeon ^[2]; ^[3]; Swanson, Daniel H. ^[1]; Johnson, Ulysses G. ^[1]; Stothard, Alicyn I. ^[1]; Lee, Jae Jin ^[2]; Poston, Anne W. ^[1]; ^[4]; ^[3]; Eoh, Hyungjin ^[2]; ^[1]

Central Michigan Univ., Mount Pleasant, MI (United States)
Univ. of Southern California, Los Angeles, CA (United States)
Univ. of Nebraska Medical Center, Omaha, NE (United States)
Univ. of Southern Maine, Portland, ME (United States)

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is the leading cause of death worldwide by infectious disease. Treatment of Mtb infection requires a six-month course of multiple antibiotics, an extremely challenging regimen necessitated by Mtb’s ability to form drug-tolerant persister cells. Mtb persister formation is dependent on the trehalose catalytic shift, a stress-responsive metabolic remodeling mechanism in which the disaccharide trehalose is liberated from cell surface glycolipids and repurposed as an internal carbon source to meet energy and redox demands. Here, using a biofilm-persister model, metabolomics, and cryo-electron microscopy (EM), we found that azidodeoxy- and aminodeoxy-d-trehalose analogues block the Mtb trehalose catalytic shift through inhibition of trehalose synthase TreS (Rv0126), which catalyzes the isomerization of trehalose to maltose. Out of a focused eight-member compound panel constructed by chemoenzymatic synthesis, the natural product 2-trehalosamine exhibited the highest potency and significantly potentiated first- and second-line TB drugs in broth culture and macrophage infection assays. We also report the first structure of TreS bound to a substrate analogue inhibitor, obtained via cryo-EM, which revealed conformational changes likely essential for catalysis and inhibitor binding that can potentially be exploited for future therapeutic development. Our results demonstrate that inhibition of the trehalose catalytic shift is a viable strategy to target Mtb persisters and advance trehalose analogues as tools and potential adjunctive therapeutics for investigating and targeting mycobacterial persistence.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 2470179

Journal Information:: ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 4 Vol. 10; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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