Antibacterial lysine analogs that target lysine riboswitches

Nat Chem Biol. 2007 Jan;3(1):44-9. doi: 10.1038/nchembio842. Epub 2006 Dec 3.

Abstract

Lysine riboswitches are bacterial RNA structures that sense the concentration of lysine and regulate the expression of lysine biosynthesis and transport genes. Members of this riboswitch class are found in the 5' untranslated region of messenger RNAs, where they form highly selective receptors for lysine. Lysine binding to the receptor stabilizes an mRNA tertiary structure that, in most cases, causes transcription termination before the adjacent open reading frame can be expressed. A lysine riboswitch conceivably could be targeted for antibacterial therapy by designing new compounds that bind the riboswitch and suppress lysine biosynthesis and transport genes. As a test of this strategy, we have identified several lysine analogs that bind to riboswitches in vitro and inhibit Bacillus subtilis growth, probably through a mechanism of riboswitch-mediated repression of lysine biosynthesis. These results indicate that riboswitches could serve as new classes of antibacterial drug targets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacillus subtilis / drug effects
  • Bacillus subtilis / genetics
  • Bacteria / drug effects
  • Bacteria / genetics
  • Gene Expression Regulation, Bacterial / drug effects
  • Gene Expression Regulation, Bacterial / genetics
  • Lysine / analogs & derivatives
  • Lysine / chemistry*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Nucleic Acid Conformation
  • RNA, Bacterial / chemistry*
  • RNA, Bacterial / drug effects
  • RNA, Bacterial / genetics*
  • Regulatory Elements, Transcriptional / drug effects*
  • Regulatory Elements, Transcriptional / genetics*

Substances

  • Anti-Bacterial Agents
  • RNA, Bacterial
  • Lysine

Associated data

  • PubChem-Substance/17388035
  • PubChem-Substance/17388036
  • PubChem-Substance/17388638
  • PubChem-Substance/17388639
  • PubChem-Substance/17388640
  • PubChem-Substance/17388641
  • PubChem-Substance/17388642
  • PubChem-Substance/17388643
  • PubChem-Substance/17388644
  • PubChem-Substance/17388645
  • PubChem-Substance/17388646
  • PubChem-Substance/17388647
  • PubChem-Substance/17388648
  • PubChem-Substance/17388649
  • PubChem-Substance/17388650
  • PubChem-Substance/17388651
  • PubChem-Substance/17388652
  • PubChem-Substance/17388653
  • PubChem-Substance/17388654
  • PubChem-Substance/17388655
  • PubChem-Substance/17388656
  • PubChem-Substance/17388657
  • PubChem-Substance/17388658
  • PubChem-Substance/17388659
  • PubChem-Substance/17388660
  • PubChem-Substance/17388661