Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB)inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections

Alex Washburn, Sanofar Abdeen, Yulia Ovechkina, Anne Marie Ray, Mckayla Stevens, Siddhi Chitre, Jared Sivinski, Yangshin Park, James Johnson, Quyen Hoang, Eli Chapman, Tanya Parish, Steven Johnson

Research output: Contribution to journalArticle

Abstract

Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10)chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB)virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria.

Original languageEnglish (US)
JournalBioorganic and Medicinal Chemistry Letters
DOIs
StatePublished - Jan 1 2019

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Polypharmacology
Chaperonins
Mycobacterium Infections
Protein Tyrosine Phosphatases
Mycobacterium tuberculosis
Bacteria
Chaperonin 10
Granuloma
Protein folding
Tuberculosis
Molecular Chaperones
Virulence Factors
Chaperonin 60
Housekeeping
Protein Folding
Standard of Care
Patient Compliance
Cytokines
Anti-Bacterial Agents
Homeostasis

Keywords

  • Antibiotics
  • Chaperonin
  • GroEL
  • GroES
  • HSP10
  • HSP60
  • Molecular chaperone
  • Mycobacterium tuberculosis
  • Phosphatases
  • Polypharmacology
  • Proteostasis
  • Small molecule inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB)inhibitors : A polypharmacology strategy for treating Mycobacterium tuberculosis infections. / Washburn, Alex; Abdeen, Sanofar; Ovechkina, Yulia; Ray, Anne Marie; Stevens, Mckayla; Chitre, Siddhi; Sivinski, Jared; Park, Yangshin; Johnson, James; Hoang, Quyen; Chapman, Eli; Parish, Tanya; Johnson, Steven.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2019.

Research output: Contribution to journalArticle

Washburn, Alex ; Abdeen, Sanofar ; Ovechkina, Yulia ; Ray, Anne Marie ; Stevens, Mckayla ; Chitre, Siddhi ; Sivinski, Jared ; Park, Yangshin ; Johnson, James ; Hoang, Quyen ; Chapman, Eli ; Parish, Tanya ; Johnson, Steven. / Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB)inhibitors : A polypharmacology strategy for treating Mycobacterium tuberculosis infections. In: Bioorganic and Medicinal Chemistry Letters. 2019.
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