Amrita Singh, Samantha Ottavi, Inna Krieger, Kyle Planck, Andrew Perkowski, Takushi Kaneko, Andrew M Davis, Christine Suh, David Zhang, Laurent Goullieux, Alexander Alex, Christine Roubert, Mark Gardner, Marian Preston, Dave M Smith, Yan Ling, Julia Roberts, Bastien Cautain, Anna Upton, Christopher B Cooper, Natalya Serbina, Zaid Tanvir, John Mosior, Ouathek Ouerfelli, Guangli Yang, Ben S Gold, Kyu Y Rhee, James C Sacchettini, Nader Fotouhi, Jeffrey Aubé, Carl Nathan
There is a compelling need to find drugs active against Mycobacterium tuberculosis ( Mtb ). 4'-Phosphopantetheinyl transferase (PptT) is an essential enzyme in Mtb that has attracted interest as a potential drug target. We optimized a PptT assay, used it to screen 422,740 compounds, and identified raltitrexed, an antineoplastic antimetabolite, as the most potent PptT inhibitor yet reported. While trying unsuccessfully to improve raltitrexed's ability to kill Mtb and remove its ability to kill human cells, we learned three lessons that may help others developing antibiotics...
March 15, 2024: Science Advances