New Host-Directed Therapeutics for the Treatment of Clostridioides difficile Infection.

MBio
Jourdan A AnderssonSara M Dann

Abstract

Frequent and excessive use of antibiotics primes patients to Clostridioides difficile infection (CDI), which leads to fatal pseudomembranous colitis, with limited treatment options. In earlier reports, we used a drug repurposing strategy and identified amoxapine (an antidepressant), doxapram (a breathing stimulant), and trifluoperazine (an antipsychotic), which provided significant protection to mice against lethal infections with several pathogens, including C. difficile However, the mechanisms of action of these drugs were not known. Here, we provide evidence that all three drugs offered protection against experimental CDI by reducing bacterial burden and toxin levels, although the drugs were neither bacteriostatic nor bactericidal in nature and had minimal impact on the composition of the microbiota. Drug-mediated protection was dependent on the presence of the microbiota, implicating its role in evoking host defenses that promoted protective immunity. By utilizing transcriptome sequencing (RNA-seq), we identified that each drug increased expression of several innate immune response-related genes, including those involved in the recruitment of neutrophils, the production of interleukin 33 (IL-33), and the IL-22 signaling pat...Continue Reading

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Datasets Mentioned

BETA
GSE144291

Methods Mentioned

BETA
ELISA
PCR
enzyme-linked immunosorbent assay
PCA
RNA-seq
Amplicon Seq
protein assay

Software Mentioned

Partek
Ingenuity Pathways Analysis ( IPA )
GraphPad
UPARSE
STAR
Partek Genomics Suite
Partek Flow server
QIIME
Morpheus
GraphPad Prism

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