An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance

Jordan Hosfelt, Aweon Richards, Meng Zheng, Carolina Adura, Brock Nelson, Amy Yang, Allison Fay, William Resager, Beatrix Ueberheide, J. Fraser Glickman, Tania J. Lupoli

Research output: Contribution to journalArticlepeer-review

Abstract

DnaK is the bacterial homolog of Hsp70, an ATP-dependent chaperone that helps cofactor proteins to catalyze nascent protein folding and salvage misfolded proteins. In the pathogen Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), DnaK and its cofactors are proposed antimycobacterial targets, yet few small-molecule inhibitors or probes exist for these families of proteins. Here, we describe the repurposing of a drug called telaprevir that is able to allosterically inhibit the ATPase activity of DnaK and to prevent chaperone function by mimicking peptide substrates. In mycobacterial cells, telaprevir disrupts DnaK- and cofactor-mediated cellular proteostasis, resulting in enhanced efficacy of aminoglycoside antibiotics and reduced resistance to the frontline TB drug rifampin. Hence, this work contributes to a small but growing collection of protein chaperone inhibitors, and it demonstrates that these molecules disrupt bacterial mechanisms of survival in the presence of different antibiotic classes.

Original languageEnglish (US)
Pages (from-to)854-869.e9
JournalCell Chemical Biology
Volume29
Issue number5
DOIs
StatePublished - May 19 2022

Keywords

  • antibiotic adjuvants
  • chaperones
  • cofactors
  • DnaJ
  • DnaK
  • Hsp70
  • mycobacteria
  • proteostasis
  • resistance
  • tuberculosis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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