Advancing therapeutics for recurrent clostridioides difficile infections: an overview of vowst's FDA approval and implications.

Clostridioides difficile infections (CDI) are a leading cause of healthcare-associated infections with a high relapse rate. Current treatment guidelines recommend fidaxomicin as the primary therapy for initial CDI episodes and suggest alternative approaches for recurrent episodes, including fecal microbiota transplantation (FMT). This paper explores the recent approval of Vowst, a novel oral FMT drug, by the United States Food and Drug Administration (FDA) as a prophylactic therapy to prevent recurrent CDIs. Vowst comprises a formulation of live fecal microbiota spores and works by reestablishing the disrupted gut microbiota, limiting C. difficile spore germination, and promoting microbiome repair. Furthermore, this paper will discuss the product's approval journey and the uncertainties regarding its efficacy in CDI patients beyond the ones who participated in the clinical trials, pharmacovigilance, cost estimates, and the need for a more stringent donor screening process. Overall, Vowst's approval marks a significant step forward in the prevention of recurrent CDI infections with various beneficial implications for future gastroenterology.

The role of cholesterol recognition (CARC/CRAC) mirror codes in the allosterism of the human organic cation transporter 2 (OCT2, SLC22A2).

The human organic cation transporter 2 (OCT2) is a multispecific transporter with cholesterol-dependent allosteric features. The present work elucidates the role of evolutionarily conserved cholesterol recognition/interaction amino acid consensus sequences (CRAC and CARC) in the allosteric binding to 1-methyl-4-phenylpyridinium (MPP+) in human embryonic kidney 293 cells stably or transiently expressing OCT2. Molecular blind simulations docked two mirroring cholesterol molecules in the 5th putative transmembrane domain, where a CARC and a CRAC sequence lie. The impact of the conserved amino acids that may constitute the CARC/CRAC mirror code was studied by alanine-scanning mutagenesis. At a saturating extracellular concentration of substrate, at which the impact of cholesterol depletion is maximal, five mutants transported MPP+ at a significantly lower rate than the wild-type OCT2 (WT), resembling the behavior of the WT upon cholesterol depletion. MPP+ influx rate as a function of the extracellular concentration of substrate was measured for the mutants R234A, R235A, L252A and R263A. R234A kinetic behavior was similar to that of the WT, whereas R235A, L252A and R263A activity shifted from allosteric to one-binding site kinetics, very much like the WT upon cholesterol depletion. The impact of cholesterol on protein thermal stability was assessed for WT, R234A and R263A. While the thermal stability of WT and R234A was improved by the supplementation with cholesterol, R263A was not sensitive to the presence of cholesterol. To conclude, the disruption of the CARC/CRAC mirror code in the 5th putative transmembrane domain is sufficient to abolish the allosteric interaction between OCT2 and MPP+.