Date of Award


Degree Name

Doctor of Philosophy


Biological Sciences

First Advisor

Dr. Bruce Bejcek

Second Advisor

Dr. Alexander Enyedi

Third Advisor

Dr. John Spitsbergen

Fourth Advisor

Dr. John Geiser


The first potent inhibitors of glutamate racemase (Murl) enzyme that show whole cell antibacterial activity are described. Optically pure 4-substituted D-glutamic acid analogues with (2R,4S) stereochemistry and bearing aryl-, heteroaryl-, cinnamyl- or biaryl-methyl substituents represent a novel class of glutamate racemase inhibitors. Exploration of the D-Glu core led to the identification of lead compounds (-)-8 and 10. 2- Naphthylmethyl derivative 10 was found to be a potent competitive inhibitor of glutamate racemase activity (Ki =16 nM, CD assay; IC50 = 0.1 µg/mL HPLC assay).

Thorough SAR studies led to benzothienyl derivatives such as 69 and 74 with increased potency (IC50 = 0.036 and 0.01 µg/mL, respectively, HPLC assay). These compounds showed potent whole cell antibacterial activity against S.pneumoniae PN-R6, and good correlation with the enzyme assay. Compounds 69, 74 and biaryl derivative 52 showed efficacy in an in vivo murine thigh infection model against S. pneumoniae. Data described herein suggests that glutamate racemase may be a viable target for developing new antibacterial agents.

Access Setting

Dissertation-Campus Only

Restricted to Campus until