Antibacterial lysine analogs that target lysine riboswitches.
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.
Blount
Kenneth F
KF
Department of Molecular, Cellular and Developmental Biology, Yale University, 266 Whitney Avenue, KBT 506, New Haven, Connecticut 06520, USA.
Wang
Joy Xin
JX
Lim
Jinsoo
J
Sudarsan
Narasimhan
N
Breaker
Ronald R
RR
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000235:genetics; D001419:Bacteria / Q000187:drug effects / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D012329:RNA, Bacterial / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects* / Q000235:genetics*
D000900:Anti-Bacterial Agents; D012329:RNA, Bacterial; D008239:Lysine