Conserved Oligopeptide Permeases Modulate Sporulation Initiation in Clostridium difficile

Edwards, Adrianne N.; Nawrocki, Kathryn L.; McBride, Shonna M.

doi:10.1128/iai.02323-14

Cited by 95 publications

(170 citation statements)

References 100 publications

(145 reference statements)

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“…Isolates D and E1 also shared an SNV in the oligotransport-ATP binding domain of oppF (Table 4), which belongs to an operon of oligopeptide permease (opp) genes that are involved in regulating sporulation (among other processes) in some species of Bacillus and Clostridium (18,19). In vitro sporulation studies on all isolates revealed no significant difference (data not shown) in the rate of sporulation between isolate D and E1 and all other isolates.…”

Section: Discussionmentioning

confidence: 99%

“…However, these data may not be representative of in vivo sporulation characteristics; therefore, it cannot be conclusively proven that this SNV had no effect. The opp operon is involved in other processes in other organisms, for example, competence in Bacillus and Streptococcus species, plasmid transfer in Enterococcus faecalis, and the expression of virulence factors in Bacillus thuringiensis (18,20). Therefore, SNVs in this region may have a yetundiscovered role in C. difficile virulence and could present a further avenue of research.…”

Section: Discussionmentioning

confidence: 99%

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Coinfection and Emergence of Rifamycin Resistance during a Recurrent Clostridium difficile Infection

et al. 2016

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c Clostridium difficile (Peptoclostridium difficile) is a common health care-associated infection with a disproportionately high incidence in elderly patients. Disease symptoms range from mild diarrhea to life-threatening pseudomembranous colitis. Around 20% of patients may suffer recurrent disease, which often requires rehospitalization of patients. C. difficile was isolated from stool samples from a patient with two recurrent C. difficile infections. PCR ribotyping, whole-genome sequencing, and phenotypic assays were used to characterize these isolates. Genotypic and phenotypic screening of C. difficile isolates revealed multiple PCR ribotypes present and the emergence of rifamycin resistance during the infection cycle. Understanding both the clinical and bacterial factors that contribute to the course of recurrent infection could inform strategies to reduce recurrence. (This study has been registered at ClinicalTrials.gov under registration no. NCT01670149.) C lostridium difficile (Peptoclostridium difficile) is a common health care-associated infection with a disproportionately high incidence in elderly patients. Recurrent Clostridium difficile infection (CDI) is known to occur in approximately 20% of patients following withdrawal of treatment antibiotics (1); however, this may rise to 65% if a patient has a history of CDI (2). Recurring CDI not only causes distress to patients but is also a substantial burden on the health care system due to the increased cost (3) associated with possible prolonged stay or readmission of a patient to the hospital and the readministration of diagnostic tests and antibiotics (4). Collaborations between clinicians and researchers are contributing to knowledge of how both the host and bacterium are affecting recurrent disease in order to reduce recurrence rates through personalized patient care regimens (5).In this study, multiple stool samples from a patient enrolled in a clinical trial were collected and C. difficile was isolated. The strains isolated from these samples were then phenotypically and genotypically characterized to deduce if changes in the C. difficile strain genotype and phenotype could have contributed to recurrent infection.Case. A male participant (01008), aged 85 years, had a history of chronic kidney disease and was on multiple long-term medications, including bumetanide, candesartan, digoxin, simvastatin, doxazosin, ferrous fumarate, and prednisolone. Three months prior to trial enrollment the participant received cefuroxime and gentamicin for a urinary tract infection. One month prior to trial enrollment he was admitted to the hospital, where he received clindamycin (both orally and intravenously) for an infected leg ulcer.In June 2013, after being readmitted to the hospital, he was diagnosed with CDI (Table 1, sample A), treated with metronidazole (MET), and discharged. He was diagnosed again with CDI in July (Table 1, sample B) and was treated again with MET.In July 2013, within 5 days of cessation of successful treatment of CDI with MET (defined as ce...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Coinfection and Emergence of Rifamycin Resistance during a Recurrent Clostridium difficile Infection

et al. 2016

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“…It is speculated that oligopeptides taken up as nutrients are responsible for this inverse regulation of virulence of C. difficile. 55 In case of the facultative intracellular pathogen Listeria monocytogenes, the gene oppA is required for survival inside macrophages besides providing nutrition. 56 …”

Section: Gram Positive Pathogensmentioning

confidence: 99%

Bacterial peptide transporters: Messengers of nutrition to virulence

2016

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Bacteria possess numerous peptide transporters for importing peptides as nutrients. However, these peptide transporters are now consistently reported to play a role in the virulence of various bacterial pathogens. Their ability to transport peptides has implications in antibacterial therapy as well. Therefore, it would be instrumental to have complete knowledge about the role of peptide transporters in mediating this cross connection between metabolism and pathogenesis. Studies on various peptide transporters in bacterial pathogens have improved our understanding of this field. In this review, we have given an overview of the functioning of bacterial peptide transporters and their contribution in virulence of major bacterial pathogens.

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“…In previous work, we found that the two oligopeptide transporters Opp and App inhibit the initiation of sporulation in C. difficile (19). It was proposed that Opp and App inhibit sporulation by importing peptides into the cell.…”

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confidence: 99%

“…All cultures were anaerobically incubated at 37°C while being monitored for growth and spore production. Micrographs were taken and enumerated as previously described (19), with minor modifications. Approximately 24 h following the start of stationary phase (T 24 ), 1-ml samples were taken from the cultures.…”

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confidence: 99%

CodY-Dependent Regulation of Sporulation in Clostridium difficile

et al. 2016

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Clostridium difficile must form a spore to survive outside the gastrointestinal tract. The factors that trigger sporulation in C. difficile remain poorly understood. Previous studies have suggested that a link exists between nutritional status and sporulation initiation in C. difficile. In this study, we investigated the impact of the global nutritional regulator CodY on sporulation in C. difficile strains from the historical 012 ribotype and the current epidemic 027 ribotype. Sporulation frequencies were increased in both backgrounds, demonstrating that CodY represses sporulation in C. difficile. The 027 codY mutant exhibited a greater increase in spore formation than the 012 codY mutant. To determine the role of CodY in the observed sporulation phenotypes, we examined several factors that are known to influence sporulation in C. difficile. Using transcriptional reporter fusions and quantitative reverse transcription-PCR (qRT-PCR) analysis, we found that two loci associated with the initiation of sporulation, opp and sinR, are regulated by CodY. The data demonstrate that CodY is a repressor of sporulation in C. difficile and that the impact of CodY on sporulation and expression of specific genes is significantly influenced by the strain background. These results suggest that the variability of CodY-dependent regulation is an important contributor to virulence and sporulation in current epidemic isolates. This report provides further evidence that nutritional state, virulence, and sporulation are linked in C. difficile. IMPORTANCEThis study sought to examine the relationship between nutrition and sporulation in C. difficile by examining the global nutritional regulator CodY. CodY is a known virulence and nutritional regulator of C. difficile, but its role in sporulation was unknown. Here, we demonstrate that CodY is a negative regulator of sporulation in two different ribotypes of C. difficile. We also demonstrate that CodY regulates known effectors of sporulation, Opp and SinR. These results support the idea that nutrient limitation is a trigger for sporulation in C. difficile and that the response to nutrient limitation is coordinated by CodY. Additionally, we demonstrate that CodY has an altered role in sporulation regulation for some strains.

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Conserved Oligopeptide Permeases Modulate Sporulation Initiation in Clostridium difficile

Cited by 95 publications

References 100 publications

Coinfection and Emergence of Rifamycin Resistance during a Recurrent Clostridium difficile Infection

Coinfection and Emergence of Rifamycin Resistance during a Recurrent Clostridium difficile Infection

Bacterial peptide transporters: Messengers of nutrition to virulence

CodY-Dependent Regulation of Sporulation in Clostridium difficile

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