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Development of Novel Small Molecule Antibiotics against T‐box Riboswitches in Gram‐positive Bacteria
Author(s) -
Väre Ville Yrjö Petteri,
Todd Gabrielle C.,
Frohlich Kyla M.,
Bell Janeen T.,
Weintraub Spencer F.,
Agris Paul F.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.613.7
Subject(s) - riboswitch , biology , bacterial transcription , rna , operon , transfer rna , bacteria , transcription (linguistics) , chemistry , biochemistry , rna polymerase , escherichia coli , genetics , gene , non coding rna , linguistics , philosophy
T‐box riboswitches are RNA regulatory elements located at the 5′‐untranslated region (5′‐UTR) found in numerous gram‐positive bacteria that control several genes involved in tRNA aminoacylation, as well as amino acid metabolism and transport. T‐boxes function by recognizing the charge status of their cognate tRNA ligand: uncharged tRNA stabilizes an antiterminator complex when bound, allowing transcription of the downstream operon, whereas charged tRNA is unable to fully bind the T‐box, allowing a terminator loop to persist and halt transcription. Given that T‐boxes are found exclusively in gram‐positive bacteria and share highly conserved regions necessary for tRNA binding, this RNA regulatory element represents a prime target for antibacterial drug development. Using docking studies to known atomic‐resolution T‐box structures, 43 putative antibacterial compounds representing distinct chemical families were selected for further characterization. Antibacterial microdilution studies resulted in a moderately active hit compound (PKZ18) that has been selected for antibacterial drug development. Characterization studies demonstrate that PKZ18 is refractory to resistance, displays low cytotoxicity, and possesses activity against a wide range of gram‐positive bacteria, including clinical isolates of Staphylococcus aureus , Streptococcus pyogenes , and Clostridium difficile . Mechanism of action studies confirm binding of PKZ18 to both glycine and tyrosine T‐boxes. Structure‐activity relationship (SAR) studies have revealed essential moieties for both selectivity as well as activity. Hit‐to‐lead optimization of PKZ18 by medicinal chemistry and further SAR studies is on‐going.