title: Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity.
abstract: The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a high-throughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans-translation tagging reaction with an IC50 = 0.9 µM. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics.
authors.affiliation: Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Nitya S
authors.initials: NS
authors.lastname: Ramadoss
authors.forename: John N
authors.initials: JN
authors.lastname: Alumasa
authors.forename: Lin
authors.initials: L
authors.lastname: Cheng
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Sharon
authors.initials: S
authors.lastname: Li
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Chambers
authors.forename: Hoon
authors.initials: H
authors.lastname: Chang
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.forename: Achim
authors.initials: A
authors.lastname: Brinker
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Engels
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Keiler
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology; D001681:Biological Assay; D018388:Codon, Terminator / Q000235:genetics; D015195:Drug Design; D024881:Drug Resistance, Bacterial / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D015723:Gene Library; D006801:Humans; D008156:Luciferases / Q000235:genetics; D009690:Nucleic Acid Conformation; D014176:Protein Biosynthesis / Q000502:physiology*; D012329:RNA, Bacterial / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics; D054852:Small Molecule Libraries
chemical_list: D000900:Anti-Bacterial Agents; D018388:Codon, Terminator; D012329:RNA, Bacterial; D054852:Small Molecule Libraries; D008156:Luciferases
keywords: antibiotic target; non-stop translation; tmRNA