Patrick Keane, Graduate Student, Dowd Lab, GW Department of Chemistry

The Department of Chemistry Presents:  Patrick Keane, Graduate Student, Dowd Lab, GW Department of Chemistry.  

The continuing rise of antimicrobial resistance worldwide has driven the need for novel antimicrobials. The methylerythritol phosphate (MEP) pathway has been of great interest for developing antimicrobials due to its essentiality in synthesizing the isoprenoid building blocks, isopentenyl pyrophosphate (IPP) and dimethylallylpyrophosphate (DMAPP), in bacteria and some eukaryotic parasites while being completely absent in humans. We focused on two enzymes of the MEP pathway in in particular, 1-deoxy-D-xylulose-5-phosphate reductor-isomerase (DXR) and 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (IspH). Several natural productsexist that are known DXR inhibitors including fosmidomycin and FR900098, however they are hindered by their poor cell permeability. Additionally, a number ofIspH inhibitors have been developed that have demonstrated nanomolar potency but contain the polar and labile pyrophosphate moiety that negatively affect cellpenetration and stability. We hope to improve upon the fosmidomycin scaffold through prodrug strategies that improve whole cell activity through targeting of DXR.We also hope to explore the SAR of IspH inhibitors to improve upon both potency and lipophilicity.

BIO

Patrick earned my Bachelors in Chemistry at McDaniel College in Westminster Maryland. Patrick joined the Dowd lab in the Fall of 2022 and have been working on the synthesis of novel prodrugs of DXR inhibitors and have started work on the synthesis of IspH inhibitors.