The Lupoli Group, along with colleagues at NYU Langone, Sloan Kettering and Rockefeller, have revealed the potential to repurpose teleprevir, a drug used to treat Hepatitis, finding that the antiviral blocks the function of essential proteins in bacteria. The study, entitled "An allosteric inhibitor of bacterial Hsp70 chaperone potentiates antibiotics and mitigates resistance," was published in Cell Chemical Biology. NYU Chemistry contributors include first-author Jordan Hosfeldt, Aweon Richards, Meng Zheng, Brock Nelson and Amy Yang, as well as study lead Assistant Professor Tania Lupoli. NYU Research Highlights features the study in "Hepatits Drug Increases Antibiotic Potency, Limits Antibiotic Resistance" and it has been picked up by Genetic Engineering & Biotechnology News in a piece called, "Hepatitis Drug Boosts Bacterial Antibiotic Sensitivity, Dampens Resistance to Frontline TB Therapy" as well.
Summary: 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.
This Research was supported by the National Science Foundation and the National Institutes of Health.