Protein Cofactor Mimics Disrupt Essential Chaperone Function in Stressed Mycobacteria

Brock Nelson, Seong Ho Hong, Tania J. Lupoli

Research output: Contribution to journalArticlepeer-review


Bacterial DnaK is an ATP-dependent molecular chaperone important for maintaining cellular proteostasis in concert with cofactor proteins. The cofactor DnaJ delivers nonnative client proteins to DnaK and activates its ATPase activity, which is required for protein folding. In the bacterial pathogen Mycobacterium tuberculosis, DnaK is assisted by two DnaJs, DnaJ1 and DnaJ2. Functional protein-protein interactions (PPIs) between DnaK and at least one DnaJ are essential for survival of mycobacteria; hence, these PPIs represent untapped antibacterial targets. Here, we synthesize peptide-based mimetics of DnaJ1 and DnaJ2 N-terminal domains as rational inhibitors of DnaK- cofactor interactions. We find that covalently stabilized DnaJ mimetics are capable of disrupting DnaK-cofactor activity in vitro and prevent mycobacterial recovery from proteotoxic stress in vivo, leading to cell death. Since chaperones and cofactors are highly conserved, we anticipate these results will inform the design of other mimetics to modulate chaperone function across cell types.

Original languageEnglish (US)
Pages (from-to)901-910
Number of pages10
JournalACS Infectious Diseases
Issue number5
StatePublished - May 13 2022


  • DnaK
  • J-domain protein
  • molecular chaperones
  • mycobacteria
  • proteomimetic
  • proteostasis
  • Mycobacterium tuberculosis/metabolism
  • Bacterial Proteins/genetics
  • Molecular Chaperones/metabolism
  • Heat-Shock Proteins/genetics

ASJC Scopus subject areas

  • Infectious Diseases


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