Title | Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase. |
Publication Type | Journal Article |
Year of Publication | 2024 |
Authors | Singh A, Ottavi S, Krieger I, Planck K, Perkowski A, Kaneko T, Davis AM, Suh C, Zhang D, Goullieux L, Alex A, Roubert C, Gardner M, Preston M, Smith DM, Ling Y, Roberts J, Cautain B, Upton A, Cooper CB, Serbina N, Tanvir Z, Mosior J, Ouerfelli O, Yang G, Gold BS, Rhee KY, Sacchettini JC, Fotouhi N, Aubé J, Nathan C |
Journal | Sci Adv |
Volume | 10 |
Issue | 11 |
Pagination | eadj6406 |
Date Published | 2024 Mar 15 |
ISSN | 2375-2548 |
Keywords | Bacterial Proteins, Humans, Mycobacterium tuberculosis, Neoplasms, Quinazolines, Thiophenes, Thymidylate Synthase, Transferases (Other Substituted Phosphate Groups) |
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. |
DOI | 10.1126/sciadv.adj6406 |
Alternate Journal | Sci Adv |
PubMed ID | 38489355 |
PubMed Central ID | PMC10942122 |
Grant List | P30 CA008748 / CA / NCI NIH HHS / United States R01 AI155510 / AI / NIAID NIH HHS / United States |
Submitted by ljc4002 on August 22, 2025 - 9:43am