Hosfelt Jordan, Richards Aweon, Zheng Meng, Adura Carolina, Nelson Brock, Yang Amy, Fay Allison, Resager William, Ueberheide Beatrix, Glickman J Fraser, Lupoli Tania J
Department of Chemistry, New York University, New York, NY 10003, USA.
High-Throughput and Spectroscopy Resource Center, The Rockefeller University, New York, NY 10065, USA.
Cell Chem Biol. 2022 May 19;29(5):854-869.e9. doi: 10.1016/j.chembiol.2021.11.004. Epub 2021 Nov 23.
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.
DnaK是热休克蛋白70（Hsp70）的细菌同源物，Hsp70是一种依赖ATP的伴侣蛋白，可帮助辅助因子蛋白催化新生蛋白折叠并挽救错误折叠的蛋白。在结核病（TB）的病原体结核分枝杆菌中，DnaK及其辅助因子被认为是抗分枝杆菌的靶点，但针对这些蛋白家族的小分子抑制剂或探针却很少。在此，我们描述了一种名为特拉匹韦的药物的重新利用，该药物能够变构抑制DnaK的ATP酶活性，并通过模拟肽底物来阻止伴侣蛋白功能。在分枝杆菌细胞中，特拉匹韦破坏了DnaK和辅助因子介导的细胞蛋白质稳态，导致氨基糖苷类抗生素的疗效增强，并降低了对一线抗结核药物利福平的耐药性。因此，这项工作为数量虽少但不断增加的蛋白质伴侣抑制剂库做出了贡献，并且表明这些分子在存在不同抗生素类别的情况下会破坏细菌的生存机制。
