Oral Multiple Sclerosis Drugs Inhibit theIn vitroGrowth of Epsilon Toxin Producing Gut Bacterium,Clostridium perfringens.
There are currently three oral medications approved for the treatment of multiple sclerosis (MS). Two of these medications, Fingolimod, and Teriflunomide, are considered to be anti-inflammatory agents, while dimethyl fumarate (DMF) is thought to trigger a robust antioxidant response, protecting vulnerable cells during an MS attack. We previously proposed that epsilon toxin from the gut bacterium,Clostridium perfringens, may initiate newly forming MS lesions due to its tropism for blood-brain barrier (BBB) vasculature and central nervous system myelin. Because gut microbiota will be exposed to these oral therapies prior to systemic absorption, we sought to determine if these compounds affectC. perfringensgrowthin vitro. Here we show that Fingolimod, Teriflunomide, and DMF indeed inhibitC. perfringensgrowth. Furthermore, several compounds similar to DMF in chemical structure, namely α, β unsaturated carbonyls, also known as Michael acceptors, inhibitC. perfringens. Sphingosine, a Fingolimod homolog with known antibacterial properties, proved to be a potentC. perfringensinhibitor with a Minimal Inhibitory Concentration similar to that of Fingolimod. These findings suggest that currently approved oral MS therapies and structurally related compounds possess antibacterial properties that may alter the gut microbiota. Moreover, inhibition ofC. perfringensgrowth and resulting blockade of epsilon toxin production may contribute to the clinical efficacy of these disease-modifying drugs.
Laboratory of Bacterial Pathogenesis and Immunology, Rockefeller University New York, NY, USA.
Kareem R
KR
Rumah
The Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medical College New York, NY, USA.
Timothy K
TK
Vartanian
Laboratory of Bacterial Pathogenesis and Immunology, Rockefeller University New York, NY, USA.
Vincent A
VA
Fischetti
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003016:Clostridium perfringens / Q000187:drug effects* / Q000254:growth & development*; D003437:Crotonates / Q000494:pharmacology*; D000069462:Dimethyl Fumarate / Q000494:pharmacology*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D006885:Hydroxybutyrates; D008826:Microbial Sensitivity Tests; D009570:Nitriles; D014052:Toluidines / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D003437:Crotonates; D006885:Hydroxybutyrates; D009570:Nitriles; D014052:Toluidines; C527525:teriflunomide; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride
Clostridium perfringens; anti-bacterial agents; microbiome; multiple sclerosis; oral therapies