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Updated: Jul 3, 2025
Cefoperazone-treated Mouse Model of Clinically-relevant Clostridium difficile Strain R20291
Published on: December 10, 2016
The pH-responsive SmrR-SmrT system modulates C. difficile antimicrobial resistance, spore formation, and toxin
Daniela Wetzel1, Zavier A Carter1, Marcos P Monteiro1
1Department of Microbiology and Immunology, Emory University School of Medicine, Emory Antibiotic Resistance Center, Atlanta, Georgia, USA.
Abstract:
Clostridioides difficile is an anaerobic gastrointestinal pathogen that spreads through the environment as dormant spores. To survive, replicate, and sporulate in the host intestine, C. difficile must adapt to a variety of conditions in its environment, including changes in pH, the availability of metabolites, host immune factors, and a diverse array of other species. Prior studies showed that changes in intestinal conditions, such as pH, can affect C. difficile toxin production, spore formation, and cell survival. However, little is understood about the specific genes and pathways that facilitate environmental adaptation and lead to changes in C. difficile cell outcomes. In this study, we investigated two genes, CD2505 and CD2506, that are differentially regulated by pH to determine if they impact C. difficile growth and sporulation. Using deletion mutants, we examined the effects of both genes (herein smrR and smrT) on sporulation frequency, toxin production, and antimicrobial resistance. We determined that SmrR is a repressor of smrRT that responds to pH and suppresses sporulation and toxin production through regulation of the SmrT transporter. Further, we showed that SmrT confers resistance to erythromycin and lincomycin, establishing a connection between the regulation of sporulation and antimicrobial resistance.IMPORTANCEClostridioides difficile is a mammalian pathogen that colonizes the large intestine and produces toxins that lead to severe diarrheal disease. C. difficile is a major threat to public health due to its intrinsic resistance to antimicrobials and its ability to form dormant spores that are easily spread from host to host. In this study, we examined the contribution of two genes, smrR and smrT, on sporulation, toxin production, and antimicrobial resistance. Our results indicate that SmrR represses smrT expression, while production of SmrT increases spore and toxin production, as well as resistance to antibiotics.
Insights
Researchers identified two genes, smrR and smrT, that help Clostridioides difficile adapt to its environment. SmrR controls smrT, which influences spore and toxin production, and antibiotic resistance in C. difficile.
Area of Science:
- Microbiology
- Molecular Biology
- Pathogenesis
Background:
- Clostridioides difficile is an anaerobic gastrointestinal pathogen known for its ability to form dormant spores.
- Environmental conditions like pH significantly impact C. difficile's toxin production, sporulation, and survival.
- Understanding the genetic basis of C. difficile's environmental adaptation is crucial for combating its pathogenicity.
Purpose of the Study:
- To investigate the roles of two pH-regulated genes, CD2505 (smrR) and CD2506 (smrT), in C. difficile growth and sporulation.
- To determine the impact of smrR and smrT on C. difficile sporulation frequency, toxin production, and antimicrobial resistance.
Main Methods:
- Construction and analysis of deletion mutants for smrR and smrT in C. difficile.
- Quantification of sporulation frequency and toxin production in mutant strains.
- Assessment of antimicrobial resistance profiles for C. difficile strains with altered smrR and smrT expression.
Main Results:
- SmrR acts as a repressor of the smrRT operon, responding to environmental pH.
- SmrR negatively regulates sporulation and toxin production by controlling the SmrT transporter.
- SmrT expression enhances C. difficile spore and toxin production and confers resistance to erythromycin and lincomycin.
Conclusions:
- SmrR and SmrT play significant roles in C. difficile adaptation, linking environmental sensing to virulence and survival.
- The SmrRT system is a novel target for understanding and potentially controlling C. difficile pathogenesis.
- The findings highlight a connection between C. difficile sporulation, toxin production, and antimicrobial resistance mechanisms.
