Thiamine pyrophosphate riboswitches are targets for the antimicrobial compound pyrithiamine.
Thiamine metabolism genes are regulated in numerous bacteria by a riboswitch class that binds the coenzyme thiamine pyrophosphate (TPP). We demonstrate that the antimicrobial action of the thiamine analog pyrithiamine (PT) is mediated by interaction with TPP riboswitches in bacteria and fungi. For example, pyrithiamine pyrophosphate (PTPP) binds the TPP riboswitch controlling the tenA operon in Bacillus subtilis. Expression of a TPP riboswitch-regulated reporter gene is reduced in transgenic B. subtilis or Escherichia coli when grown in the presence of thiamine or PT, while mutant riboswitches in these organisms are unresponsive to these ligands. Bacteria selected for PT resistance bear specific mutations that disrupt ligand binding to TPP riboswitches and derepress certain TPP metabolic genes. Our findings demonstrate that riboswitches can serve as antimicrobial drug targets and expand our understanding of thiamine metabolism in bacteria.
Sudarsan
Narasimhan
N
Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, Connecticut 06520, USA.
Cohen-Chalamish
Smadar
S
Nakamura
Shingo
S
Emilsson
Gail Mitchell
GM
Breaker
Ronald R
RR
D000890:Anti-Infective Agents / Q000494:pharmacology*; D001407:Bacillus / Q000235:genetics; D008954:Models, Biological; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D017434:Protein Structure, Tertiary; D011745:Pyrithiamine / Q000494:pharmacology*; D012329:RNA, Bacterial / Q000187:drug effects*; D013831:Thiamine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013835:Thiamine Pyrophosphate / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism
D000890:Anti-Infective Agents; D012329:RNA, Bacterial; D011745:Pyrithiamine; D013835:Thiamine Pyrophosphate; D013831:Thiamine