News & Events
Paul F. Agris, Ph.D.
Posted on February 21, 2020
Date - February 21, 2020
1:00 pm - 2:00 pm
Department of Medicine
Duke University School of Medicine
Talk Title: Discovery of novel antibiotics: The chemistry and biochemistry of a unique RNA target in Gram-positive bacteria
The emergence of multi-drug resistant bacteria in planktonic and biofilm growth necessitates identifying unique targets of intervention and compounds that inhibit their function. Gram-positive bacteria use a well-conserved tRNA-responsive transcriptional regulatory element in mRNAs, the T-box. T-boxes regulate transcription of multiple operons controlling amino acid metabolism. Using the structure of the Bacillus subtilis tyrS mRNA T-box as a model, in silico docking of 305,000 small compounds yielded 200 as potential binders. A family of compounds inhibited growth of Gram-positive bacteria including drug resistant clinical isolates at minimum inhibitory concentrations (16-64 µg/mL). Resistance developed at an extremely low mutational frequency (1.21 X 10-10). The parent compound PKZ18 inhibited in vivo transcription of glycyl-tRNA synthetase mRNA and translation of the S. aureus threonyl-tRNA synthetase protein. PKZ18 bound the Specifier Loop in vitro (Kd ~24 µM) and its core chemistry has been defined for antibacterial activity. These findings support the T-box regulatory mechanism as a new target for antibiotic discovery that may impede the emergence of resistance.