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Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase.

Amrita SinghSamantha OttaviInna V KriegerKyle PlanckAndrew J PerkowskiTakushi KanekoAndrew M DavisChristine SuhDavid ZhangLaurent GoullieuxAlexander AlexChristine RoubertMark GardnerMarian PrestonDavid M SmithYan LingJulia RobertsBastien CautainAnna M UptonChristopher B CooperNatalya SerbinaZaid TanvirJohn MosiorOuathek OuerfelliGuangli YangBen S GoldKyu Y RheeJames C SacchettiniNader FotouhiJeffrey AubeCarl F Nathan
Published in: Science advances (2024)
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.
Keyphrases
  • mycobacterium tuberculosis
  • pulmonary tuberculosis
  • crystal structure
  • structure activity relationship
  • high throughput
  • emergency department
  • binding protein
  • transcription factor
  • anti inflammatory
  • climate change