1. Academic Validation
  2. Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting

Dual-Targeting Small-Molecule Inhibitors of the Staphylococcus aureus FMN Riboswitch Disrupt Riboflavin Homeostasis in an Infectious Setting

  • Cell Chem Biol. 2017 May 18;24(5):576-588.e6. doi: 10.1016/j.chembiol.2017.03.014.
Hao Wang 1 Paul A Mann 1 Li Xiao 1 Charles Gill 1 Andrew M Galgoci 1 John A Howe 1 Artjohn Villafania 1 Christopher M Barbieri 1 Juliana C Malinverni 1 Xinwei Sher 1 Todd Mayhood 1 Megan D McCurry 1 Nicholas Murgolo 1 Amy Flattery 1 Matthias Mack 2 Terry Roemer 3
Affiliations

Affiliations

  • 1 Merck Research Laboratories, Kenilworth, NJ 07033, USA.
  • 2 Department of Biotechnology, Institute for Technical Microbiology, Hochschule Mannheim, Mannheim 68163, Germany.
  • 3 Merck Research Laboratories, Kenilworth, NJ 07033, USA. Electronic address: terry_roemer@merck.com.
Abstract

Riboswitches are bacterial-specific, broadly conserved, non-coding RNA structural elements that control gene expression of numerous metabolic pathways and transport functions essential for cell growth. As such, riboswitch inhibitors represent a new class of potential Antibacterial agents. Recently, we identified ribocil-C, a highly selective inhibitor of the flavin mononucleotide (FMN) riboswitch that controls expression of de novo riboflavin (RF, vitamin B2) biosynthesis in Escherichia coli. Here, we provide a mechanistic characterization of the Antibacterial effects of ribocil-C as well as of roseoflavin (RoF), an antimetabolite analog of RF, among medically significant Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecalis. We provide genetic, biophysical, computational, biochemical, and pharmacological evidence that ribocil-C and RoF specifically inhibit dual FMN riboswitches, separately controlling RF biosynthesis and uptake processes essential for MRSA growth and pathogenesis. Such a dual-targeting mechanism is specifically required to develop broad-spectrum Gram-positive Antibacterial agents targeting RF metabolism.

Keywords

Enterococcus faecalis; FMN riboswitch; MRSA; RibU; Staphylococcus aureus; antibiotic drug target; ribocil; riboflavin; roseoflavin; virulence factor.

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