Alyssa Teteris

SLAC National Accelerator Laboratory

ABSTRACT:

Antibiotic development is of great importance as bacteria develop more resistance to the current drugs. A good target for antibiotics is involved in vital cellular processes and will not impact human processes. In this case X-ray crystallography and activity studies were used to discover a new enzyme to target.  An important building block of DNA called thymidylate is made by an enzyme called Thymidylate synthase in humans. In many bacteria, thymidylate is made by the very different Folate Dependent Thymidylate Synthase (FDTS). Since the enzymes are very different and involved in a vital process, DNA synthesis, FDTS is a good target. Once the target is identified, the mechanism is investigated, and drug screening can begin. 

Using a library of FDA approved drugs, virtual docking studies revealed three hits out of 248 molecules when docked to Thermotoga maritima FDTS. Roxadustat, used to treat renal anemia, Tanshinone I, an anti-tumor drug, and tanshinone IIA, used to treat cardiovascular and inflammatory diseases were all identifies as possible antibiotics. Interestingly, tanshinones were known to have antimycobacterial properties, though the mechanisms are unclear. Structural differences between T. maritima and Mycobacterium tuberculosis FDTS prevented the strong interactions seen in the former when the hits were docked in the latter. 

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