@article{59fec518c83f437288840d72a88ce330,
title = "An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance",
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.",
keywords = "antibiotic adjuvants, chaperones, cofactors, DnaJ, DnaK, Hsp70, mycobacteria, proteostasis, resistance, tuberculosis",
author = "Jordan Hosfelt and Aweon Richards and Meng Zheng and Carolina Adura and Brock Nelson and Amy Yang and Allison Fay and William Resager and Beatrix Ueberheide and Glickman, {J. Fraser} and Lupoli, {Tania J.}",
note = "Funding Information: The authors would like to thank Chloe Larson and Lavoisier Ramos-Espiritu (Rockefeller), Samantha Ciervo (NYU), Gideon Yawson (NYU), and Samuel Epstein (NYU) for experimental help. We acknowledge Jason Young (McGill) for sharing chaperone plasmids, Celia Schiffer (UMass Medical School) for contributing additional HCV inhibitors, Juan Sabin (Affinimeter) for data analysis advice, Chris Dashiell (Promega) for help with reagents, and Dr. Hermann Steller (Rockefeller) for supporting the purchase of the iTC200 through an HHMI grant. T.L. acknowledges NYU for funding. J.H. acknowledges NSF GRFP grant DGE1839302. B.U. acknowledges support for the mass spectrometric experiments by a shared instrumentation grant from the NIH, 1S10OD010582-01A1, for the purchase of an Orbitrap Eclipse Tribrid mass spectrometer. Conception and design, T.L. J.H. A.R. M.Z. and C.A.; development of methodology, T.L. J.H. A.R. M.Z. A.F. C.A. B.N. F.G. and B.U.; investigation (performed biochemical, chemical, proteomic, and microbiological experiments), J.H. A.R. M.Z. C.A. B.N. A.Y. A.F. W.R. and T.L.; analysis and interpretation of data (e.g. data representation, statistical analysis, proteomics, high-throughput screening), T.L. J.H. A.R. M.Z. C.A. B.N. A.Y. W.R. B.U. C.A. and F.G.; writing of the manuscript, T.L. A.R. J.H. C.A. F.G. B.U. and A.Y.; administrative, technical, or material support, T.L. C.A. F.G. W.R. and B.U. The authors declare no competing interests. Funding Information: The authors would like to thank Chloe Larson and Lavoisier Ramos-Espiritu (Rockefeller), Samantha Ciervo (NYU), Gideon Yawson (NYU), and Samuel Epstein (NYU) for experimental help. We acknowledge Jason Young (McGill) for sharing chaperone plasmids, Celia Schiffer (UMass Medical School) for contributing additional HCV inhibitors, Juan Sabin (Affinimeter) for data analysis advice, Chris Dashiell (Promega) for help with reagents, and Dr. Hermann Steller (Rockefeller) for supporting the purchase of the iTC200 through an HHMI grant. T.L. acknowledges NYU for funding. J.H. acknowledges NSF GRFP grant DGE1839302 . B.U. acknowledges support for the mass spectrometric experiments by a shared instrumentation grant from the NIH , 1S10OD010582-01A1 , for the purchase of an Orbitrap Eclipse Tribrid mass spectrometer. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2022",
month = may,
day = "19",
doi = "10.1016/j.chembiol.2021.11.004",
language = "English (US)",
volume = "29",
pages = "854--869.e9",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "5",
}