Download MendeleyRedirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase.
Singh, A., Ottavi, S., Krieger, I., Planck, K., Perkowski, A., Kaneko, T., Davis, A.M., Suh, C., Zhang, D., Goullieux, L., Alex, A., Roubert, C., Gardner, M., Preston, M., Smith, D.M., Ling, Y., Roberts, J., Cautain, B., Upton, A., Cooper, C.B., Serbina, N., Tanvir, Z., Mosior, J., Ouerfelli, O., Yang, G., Gold, B.S., Rhee, K.Y., Sacchettini, J.C., Fotouhi, N., Aube, J., Nathan, C.(2024) Sci Adv 10: eadj6406-eadj6406
- PubMed: 38489355
- DOI: https://doi.org/10.1126/sciadv.adj6406
- Primary Citation of Related Structures:
8GKF - PubMed Abstract:
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. First, binding of raltitrexed substantially changed the configuration of the PptT active site, complicating molecular modeling of analogs based on the unliganded crystal structure or the structure of cocrystals with inhibitors of another class. Second, minor changes in the raltitrexed molecule changed its target in Mtb from PptT to dihydrofolate reductase (DHFR). Third, the structure-activity relationship for over 800 raltitrexed analogs only became interpretable when we quantified and characterized the compounds' intrabacterial accumulation and transformation.
Organizational Affiliation:
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York 10021, USA.
