Abstract

Summary

The bacterial pathogen Clostridioides difficile causes a toxin-mediated diarrheal illness and is now the leading cause of hospital-acquired infection in the US. Due to growing threats of antibiotic resistance and recurrent infection, targeting components of metabolism presents a novel approach to combat this infection. Analyses of bacterial genome-scale metabolic network reconstructions (GENREs) have identified new therapeutic targets and helped uncover properties that drive cellular behaviors. We sought to leverage this approach and thus constructed highly-curated C. difficile GENREs for a hyper-virulent isolate (R20291) as well as a historic strain (630). Growth simulations of carbon source usage revealed significant correlations between in silico and experimentally measured values (p-values ≤ 0.002, PPV ≈ 95%), and single-gene deletion analysis showed accuracies of >89% compared with transposon mutant libraries. Contextualizing these models with in situ omics datasets revealed conserved patterns of elevated proline, leucine, and valine fermentation that corresponded with significant increases in expression of multiple virulence factors during infection. Collectively, our results support that C. difficile utilizes distinct metabolic programs as infection progresses and highlights that GENREs can reveal the underpinnings of bacterial pathogenesis.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

* Abstract, Introduction, and Discussion have been updated for clarity.

Details

Title
Conserved virulence-linked metabolic reprogramming in Clostridioides difficile identified through genome-scale metabolic network analysis
Author
Jenior, Matthew L; Leslie, Jhansi L; Powers, Deborah A; Garrett, Elizabeth M; Walker, Kimberly A; Dickenson, Mary E; Petri, William A, Jr; Tamayo, Rita; Papin, Jason A
University/institution
Cold Spring Harbor Laboratory Press
Section
New Results
Publication year
2020
Publication date
Dec 15, 2020
Publisher
Cold Spring Harbor Laboratory Press
ISSN
2692-8205
Source type
Working Paper
Language of publication
English
ProQuest document ID
2506650084
Copyright
© 2020. This article is published under http://creativecommons.org/licenses/by/4.0/ (“the License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.