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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Washburn, Alex¹  Abdeen, Sanofar¹  Ovechkina, Yulia²  Ray, Anne-Marie¹  Stevens, Mckayla¹  Chitre, Siddhi¹  Sivinski, Jared³  Park, Yangshin^1,4,5  Johnson, James²  Hoang, Quyen Q.^1,4,5  Chapman, Eli³  Parish, Tanya²  Johnson, Steven M.¹ 

[1] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, 635 Barnhill Dr, Indianapolis, IN 46202 USA

[2] Infect Dis Res Inst, 1616 Eastlake Ave E, Seattle, WA 98102 USA

[3] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, 1703 E Mabel St,POB 210207, Tucson, AZ 85721 USA

[4] Indiana Univ, Sch Med, Stark Neurosci Res Inst, 320 W 15th St,Suite 414, Indianapolis, IN 46202 USA

[5] Indiana Univ Sch Med, Dept Neurol, 635 Barnhill Dr, Indianapolis, IN 46202 USA

关键词: GroEL;    GroES;    HSP60;    HSP10;    Molecular chaperone;    Chaperonin;    Proteostasis;    Phosphatases;    Small molecule inhibitors;    Mycobacterium tuberculosis;    Antibiotics;    Polypharmacology;   

DOI  :  10.1016/j.bmcl.2019.04.034

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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