@article{a857962ce6424439a04e164f920bf9bc,
title = "Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB)inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections",
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.",
keywords = "Antibiotics, Chaperonin, GroEL, GroES, HSP10, HSP60, Molecular chaperone, Mycobacterium tuberculosis, Phosphatases, Polypharmacology, Proteostasis, Small molecule inhibitors",
author = "Alex Washburn and Sanofar Abdeen and Yulia Ovechkina and Ray, {Anne Marie} and Mckayla Stevens and Siddhi Chitre and Jared Sivinski and Yangshin Park and James Johnson and Hoang, {Quyen Q.} and Eli Chapman and Tanya Parish and Johnson, {Steven M.}",
note = "Funding Information: Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS)of the National Institutes of Health (NIH)under Award Number R01GM120350. QQH and YP additionally acknowledge support by NIH grants 5R01GM111639 and 5R01GM115844. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by startup funds from the IU School of Medicine (SMJ)and the University of Arizona (EC). Technical assistance from Megha Gupta, Junitta Guzman, and Aaron Korkegian (IDRI, Seattle, WA)is also greatly appreciated. The human HSP60 expression plasmid (lacking the 26 amino acid N-terminal mitochondrial signal peptide)was generously donated by Dr. Abdussalam Azem from Tel Aviv University, Faculty of Life Sciences, Department of Biochemistry, Israel. We thank Dr. Zhong-Yin Zhang (Purdue University, West Lafayette, IN, USA)for providing the M. tuberculosis PtpB expression plasmid, with permission from Dr. Christoph Grundner (Center for Infectious Disease Research, Seattle, WA, USA), who originally developed the plasmid. Funding Information: Research reported in this publication was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH) under Award Number R01GM120350 . QQH and YP additionally acknowledge support by NIH grants 5R01GM111639 and 5R01GM115844 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by startup funds from the IU School of Medicine (SMJ) and the University of Arizona (EC). Technical assistance from Megha Gupta, Junitta Guzman, and Aaron Korkegian (IDRI, Seattle, WA) is also greatly appreciated. The human HSP60 expression plasmid (lacking the 26 amino acid N -terminal mitochondrial signal peptide) was generously donated by Dr. Abdussalam Azem from Tel Aviv University, Faculty of Life Sciences, Department of Biochemistry, Israel. We thank Dr. Zhong-Yin Zhang (Purdue University, West Lafayette, IN, USA) for providing the M. tuberculosis PtpB expression plasmid, with permission from Dr. Christoph Grundner (Center for Infectious Disease Research, Seattle, WA, USA), who originally developed the plasmid. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2019",
month = jul,
day = "1",
doi = "10.1016/j.bmcl.2019.04.034",
language = "English (US)",
volume = "29",
pages = "1665--1672",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "13",
}