Phosphorylation and functionality of CdtR in Clostridium difficile

Bilverstone, Terry W.; Minton, Nigel P.; Kuehne, Sarah A.

doi:10.1016/j.anaerobe.2019.102074

Cited by 10 publications

(8 citation statements)

References 27 publications

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“…Other subgroups of C. difficile strains, including MLST5 and MLST11 were also reported to encode CDT (Figure 7A) . 42,43 Unexpectedly, many strain types of C. difficile that were reported as CDT-negative also encode cdtR , such as MLST2, MLST8 from clade 1 (Figure 7A) . The higher prevalence of cdtR over cdtA and cdtB supports the possibility that CdtR functions beyond regulating CDT.…”

Section: Resultsmentioning

confidence: 99%

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027)Clostridioides difficile

Dong

Lin

Allen

et al. 2023

Preprint

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Clostridioides difficile (C. difficile), a leading cause of nosocomial infection, produces toxins that damage the colonic epithelium and results in colitis that varies from mild to fulminant. Variation in disease severity is poorly understood and has been attributed to host factors (age, immune competence and intestinal microbiome composition) and/or virulence differences between C. difficile strains, with some, such as the epidemic BI/NAP1/027 (MLST1) strain, being associated with greater virulence. We tested 23 MLST1(ST1) C. difficile clinical isolates for virulence in antibiotic-treated C57BL/6 mice. All isolates encoded a complete Tcd pathogenicity locus and achieved similar colonization densities in mice. Disease severity varied, however, with 5 isolates causing lethal infections, 16 isolates causing a range of moderate infections and 2 isolates resulting in no detectable disease. The avirulent ST1 isolates did not cause disease in highly susceptible Myd88-/- or germ-free mice. Genomic analysis of the avirulent isolates revealed a 69 base-pair deletion in the N-terminus of the cdtR gene, which encodes a response regulator for binary toxin (CDT) expression. Genetic deletion of the 69 base-pair cdtR sequence in the highly virulent ST1 R20291 C. difficile strain rendered it avirulent and reduced toxin gene transcription in cecal contents. Our study demonstrates that a natural deletion within cdtR attenuates virulence in the epidemic ST1 C. difficile strain without reducing colonization and persistence in the gut. Distinguishing strains on the basis of cdtR may enhance the specificity of diagnostic tests for C. difficile colitis.

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Section: Resultsmentioning

confidence: 99%

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027)Clostridioides difficile

Dong

Lin

Allen

et al. 2023

Preprint

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“…The presence of dual copies of CdtR in ST369 (C-I) is intriguing as analogous duplications in PaLoc regulators have not been documented. One of these CdtR had a mutation at a key phosphorylation site (Asp61→Asn61) and possibly shows either reduced wild-type activity or non-functionality, as seen in ST11 ( Bilverstone et al, 2019 ). This might explain the presence of a second CdtR copy.…”

Section: Discussionmentioning

confidence: 99%

Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy

Knight

Imwattana

Kullin

et al. 2021

eLife

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Clostridioides difficile infection (CDI) remains an urgent global One Health threat. The genetic heterogeneity seen across C. difficile underscores its wide ecological versatility and has driven the significant changes in CDI epidemiology seen in the last 20 years. We analysed an international collection of over 12,000 C. difficile genomes spanning the eight currently defined phylogenetic clades. Through whole-genome average nucleotide identity, and pangenomic and Bayesian analyses, we identified major taxonomic incoherence with clear species boundaries for each of the recently described cryptic clades CI-III. The emergence of these three novel genomospecies predates clades C1-5 by millions of years, rewriting the global population structure of C. difficile specifically and taxonomy of the Peptostreptococcaceae in general. These genomospecies all show unique and highly divergent toxin gene architecture, advancing our understanding of the evolution of C. difficile and close relatives. Beyond the taxonomic ramifications, this work may impact the diagnosis of CDI.

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“…The BI/NAP1/027 strain produces all three of the toxins referred to above. They damage the gut barrier leading to severe enterotoxicity in humans and the BI/NAP1/027 strain is characterized by high-level fluoroquinolone resistance (8,9).…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile

Oka

Yamaya

Kuno

et al. 2021

Antimicrob Agents Chemother

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OPS-2071 is a novel quinolone antibacterial agent characterized by low oral absorption that reduces the risk of adverse events typical of fluoroquinolone class antibiotics. The in vitro and in vivo antibacterial activities of OPS-2071 against Clostridioides difficile were evaluated in comparison to vancomycin and fidaxomicin. OPS-2071 exhibited potent antibacterial activity against 54 clinically isolated C. difficile strains with a minimum inhibitory concentration of 0.125 μg/mL (MIC50) and 0.5 μg/mL (MIC90), making it more active than vancomycin on a concentration basis (MIC50: 2 μg/mL, MIC90: 4 μg/mL) and comparable to fidaxomicin (MIC50: 0.063 μg/mL, MIC90: 8 μg/mL). OPS-2071 showed equally potent antibacterial activity against both hypervirulent and non-hypervirulent strains, while a significant difference in susceptibility to fidaxomicin was observed. Spontaneous resistance to OPS-2071 and vancomycin was not observed, however, resistance to fidaxomicin was observed at 4× MIC concentration. The mutant prevention concentration of OPS-2071 was 16-fold lower than those of fidaxomicin and vancomycin, and the post-antibiotic effect of OPS-2071 was longer than those of fidaxomicin and vancomycin. Also, OPS-2071 showed low systemic exposure, with OPS-2071 having 2.9% oral bioavailability at 1 mg/kg in rats. Furthermore, OPS-2071 showed significant in vivo efficacy at 0.0313 mg/kg/day (50% effective doses), 39.0-fold and 52.1-fold lower than those of vancomycin and fidaxomicin, respectively, in a hamster model of C. difficile infection. OPS-2071 has the potential to become a new therapeutic option for treating C. difficile infection.

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Phosphorylation and functionality of CdtR in Clostridium difficile

Cited by 10 publications

References 27 publications

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027)Clostridioides difficile

Virulence and genomic diversity among clinical isolates of ST1 (BI/NAP1/027)Clostridioides difficile

Major genetic discontinuity and novel toxigenic species in Clostridioides difficile taxonomy

In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile

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