title: Inhibitors of bacterial transcription initiation complex formation.
abstract: Antibiotic resistance is a growing global problem, with very few new compounds in development. Bacterial transcription is an underutilized target for antibiotics, which has been attributed to the similarity of the active site of RNA polymerases (RNAPs) across all domains of life and the ease with which resistance can arise through point mutation at multiple sites within this conserved region. In this study we have taken a rational approach to design a novel set of compounds that specifically target the formation of transcription initiation complexes by preventing the unique bacterial σ initiation factor from binding to RNAP. We have identified the region of RNAP to which these compounds bind and demonstrate that one compound, GKL003, has an inhibition constant in the low nanomolar range. This compound has activity against both Gram-positive and -negative organisms, including a community acquired methicillin-resistant strain of the major pathogen Staphylococcus aureus.
authors.affiliation: School of Environmental and Life Sciences, University of Newcastle , Callaghan, NSW 2308, Australia.
authors.forename: Cong
authors.initials: C
authors.lastname: Ma
authors.forename: Xiao
authors.initials: X
authors.lastname: Yang
authors.forename: Hakan
authors.initials: H
authors.lastname: Kandemir
authors.forename: Marcin
authors.initials: M
authors.lastname: Mielczarek
authors.forename: Elecia B
authors.initials: EB
authors.lastname: Johnston
authors.forename: Renate
authors.initials: R
authors.lastname: Griffith
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lewis
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy / Q000382:microbiology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D012808:Sigma Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013211:Staphylococcus aureus / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012808:Sigma Factor; D012321:DNA-Directed RNA Polymerases