Antibiotic development for multi-drug resistant bacterial strains that contribute to recurring infections in Cystic Fibrosis (CF) patients is a medically-relevant area of biochemistry and medicinal chemistry research. Interdisciplinary studies on potential activators and inhibitors of GabR and PLP-dependent GABA metabolism in the nonpathogenic species Bacillus Subtilis will enable us to modulate the GABA shunt pathway, which is under GabR-dependent transcription regulation, in the related pathogens Burkholderia cenocepacia and Burkholderia multivorans.1,2 These two species belong to the Burkholderia cepacia complex (Bcc) often associated with infections in CF patients, and synthesized ligand modulators of GabR in B. Subtilis should have a deleterious effect on viability in the pathogens. Taking advantage of the existing PLP in GabR, we start by elucidating the ligand recognition mechanisms of agonistic or antagonistic ligands, which are derived from designed inactivators of PLP-dependent aminotransferases in GabR. In B. Subtilis, B. Cenocepacia, and B. Multivorans, through site-directed mutagenesis and X-ray crystallography, we aim to provide insights into the three-dimensional structure of the Gab-R/GABA/PLP complex formed in initiating transcription of the gabTD operon. Potentially more potent analogs of 4-amino-5-fluoropentanoic acid have been designed, synthesized, and characterized for their antibiotic potential against the bacterial strains of both the nonpathogenic model and those belonging to the Bcc.References1. Belitsky, B. R.; Sonenshein, A. L. GabR, a member of a novel protein family, regulates the utilization of γ-aminobutyrate in Bacillus subtilis. Mol. Microbiol. 2002  , 45, 569-583.2. Edayathumangalam, R.; Wu, R.; Garcia, R.; Wang, Y.; Wang, W.; Kreinbring, C. A.; Bach, A.; Liao, J.; Stone, T. A.; Terwilliger, T. C.; Hoang, Q. Q.; Belitsky, B. R.; Petsko, G. A.; Ringe, D.; Liu, D. Crystal structure of Bacillus subtilis GabR, an autorepressor and transcriptional activator of gabT. Proc. Natl. Acad. Sci. U. S. A. 2013  , 110, 17820-17825,S17820/1-S17820/10.

Molecular mechanism and ligand design of a PLP/GABA-dependent bacterial transcription regulator GabR

248th National Meeting (2014)

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