Drug Interactions with Glutaredoxin Orthologues

Glutaredoxin, an enzymatic protein, is an important component of cell viability and function. It catalyzes reactions involved in DNA synthesis and innate immunity [1,4]. Glutaredoxin is also essential in antibiotic resistance in pathogenic bacterial species. Pseudomonas aeruginosa in particular is responsible for infecting the lung tissue of its human hosts, resulting in the development of pneumonia and cystic fibrosis [3]. Because glutaredoxin is pertinent in cell proliferation of eukaryotic and bacterial cells alike, medicinal fragments that take advantage of the subtle differences in protein structure of the orthologous proteins can be synthesized and enhanced to bind bacterial glutaredoxins, without inhibiting the function of the human form. This can be accomplished by exploiting the mechanisms of fragment based drug discovery using NMR techniques. A library of small potential medicinal fragments are screened against each protein to determine which interact, or bind most efficiently to the bacterial orthologues with little to no interaction with eukaryotic cells. To confirm the ability of select fragments hits to kill bacterial cells without harming human cells, MTT and MIC assays are performed to determine what concentration of fragment is needed to obtain desired therapeutic results [6,7]. These assays were performed against selected lead fragments, particularly RK207 and RK395, which can be structurally enhanced to bind even more to the bacterial orthologues. This research can potentially lead to the development of drug targets against bacterial orthologues of glutaredoxin to treat life threatening diseases caused by pathogenic species