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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

Hao Wang, Paul A Mann, Li Xiao, Charles Gill, Andrew M Galgoci, John A Howe, Artjohn Villafania, Christopher M Barbieri, Juliana C Malinverni, Xinwei Sher, Todd Mayhood, Megan D McCurry, Nicholas Murgolo, etc.

Cell Chem Biol. 2017 May 18;24(5):576-588.e6.

PMID: 28434876

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1825355563	Ribocil-C		1825355-56-3	Price

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