Disruption of the Gut Microbiome: Clostridium difficile Infection and the Threat of Antibiotic Resistance

Johanesen, Priscilla; Mackin, Kate E.; Hutton, Melanie L.; Awad, Milena M.; Larcombe, Sarah; Amy, Jacob; Lyras, Dena

doi:10.3390/genes6041347

Cited by 88 publications

(60 citation statements)

References 101 publications

(131 reference statements)

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“…It has been proposed that the use of antibiotics is the most important risk factor for CDI [4], because C. difficile is resistant to multiple antibiotics that are commonly used for treating bacterial infections in clinical settings [2,43]. Therefore, so many antibiotic resistancerelated genes harbored in the ST201 strains may contribute to the bacterial pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Peng¹,

Han²,

Meng³

et al. 2017

Preprint

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Abstract:A novel binary toxin-positive non-027, non-078 Clostridium difficile strain designated LC693 whose sequence type was ST201 was isolated from the fecal sample of a patient with severe diarrhea in China. To understand the pathogenesis basis of C. difficile ST201, this recently recovered isolate LC693 was then chosen for whole genome sequencing. The project finally generated an estimated genome size of approximately 4.07 Mbp. The genome sequence was then analyzed together with the other two ST201 strains VL-0104 and VL-0391 and compared to the epidemic 027/ST1 and 078/ST11 strains. Phylogenetic analysis demonstrated that the ST201 strains belonged to clade 3. Genome size of the three ST201 strains ranged from 4.07 Mb~4.16 Mb, with an average GC content between 28.5%~28.9%. The ST201 genomes contained more than 40 antibiotic resistance genes and 15 of them were predicted to be associated with vancomycin-resistance, suggesting that they may have a strong antibiotic resistance. The ST201 strains contained a typical clade 3 specific PaLoc with a Tn6218 element inserted, and those genes harbored on their PaLoc that participated in the toxin expression and regulation were highly homologues to the epidemic 027 and 078 strains, with the exception of tcdC. A truncated TcdC was found in the ST201 strains, which is suggestive to have a contribution to the toxin production of the ST201 strains. In addition, the ST201 strains contained intact binary toxin coding and regulation genes, which is also proposed to contribute to the virulence. Genome comparison of the ST201 strains with the epidemic 027 and 078 strain identified 641 genes specific for the C. difficile ST201, and a number of them were predicted as fitness and virulence associated genes. The identification of those genes also contributes to the pathogenesis of the ST201 strain. To our knowledge, this is the first study that the genome sequence of C. difficile ST201 was discussed in detail, and the present study would have a contribution to understanding the pathogenesis basis of C. difficile ST201.

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Section: Discussionmentioning

confidence: 99%

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Peng¹,

Han²,

Meng³

et al. 2017

Preprint

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“…[8] Although C. difficile has not yet developed significant resistance to the antibiotics most used for CDI treatment, it is highly likely that these resistance phenotypes will emerge, as has occurred through the use of clindamycin and the fluoroquinolones. [9] …”

Section: Introductionmentioning

confidence: 99%

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

Teng

Peng

et al. 2018

ChemMedChem

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Clostridium difficile infection (CDI) symptoms range from diarrhea to severe toxic megacolon and even death. Due to its rapid acquisition of resistance, C. difficile is listed as an urgent antibiotic-resistant threat, and has surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common hospital-acquired infection in the USA. To combat this pathogen, a new structural class of pseudo-peptides that exhibit antimicrobial activities could play an important role. Herein we report a set of bis-cyclic guanidine compounds that show potent antibacterial activity against C. difficile with decent selectivity. Eight compounds showed high in vitro potency against C. difficile UK6 with MIC values of 1.0 μg mL−1, and cytotoxic selectivity index (SI) values up to 37. Moreover, the most selective compound is also effective in the treatment of C. difficile-induced disease in a mouse model of CDI, and appears to be a very promising new candidate for the treatment of CDI.

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“…3 In addition, such therapies put patients at risk for associated complications including Clostridium difficile and the development of resistant organisms. 4 Despite the most aggressive treatment, prosthetic device infections frequently require the removal of the device.…”

Section: Introductionmentioning

confidence: 99%

Infection prevention using affinity polymer-coated, synthetic meshes in a pig hernia model

Blatnik

Thatiparti

Krpata

et al. 2017

Journal of Surgical Research

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Background Given concern for hernia mesh infection, surgeons often use biologic mesh which may provide reduced risk of infection but at the cost of decreased repair durability. We evaluated mesh coating to provide sustained release of antibiotics to prevent prosthetic mesh infection and also allow a durable repair. Materials and methods Cyclodextrin-based polymer was crosslinked onto multifilament polyester mesh and loaded with vancomycin (1.75 mg/cm2). Pigs received modified meshes (n =6) or normal, untreated meshes (n =4), which were implanted into acute 10 × 5 cm ventral hernia, then directly inoculated with 106 colony-forming unit (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). These were compared to animals receiving normal, uninfected mesh. All mesh was secured in an underlay bridge manner, and after 30 d, the abdominal wall was removed for quantitative bacterial culture and biomechanical analysis. Results All animals survived 30 d. All six animals with coated mesh cleared MRSA infection. The four control animals did not clear MRSA (P =0.005). Quantitative bacterial load was higher in standard mesh versus drug-delivery mesh group (2.34×104 versus 80.9 CFU/gm). These data were log10-transformed and analyzed by Welch’s t-test (P = 0.001). Minimum number of CFUs detectable by assay (300) was used instead of zero. Biomechanical analysis of controls (1.82 N/mm infected; 1.71 N/mm uninfected) showed no difference to the modified meshes (1.31 N/mm) in tissue integration (P = 0.15). Conclusions We successfully prevented synthetic mesh infection in a pig model using a cyclodextrin-based polymer to locally deliver vancomycin to the hernia repair site and clearing antibiotic-resistant bacteria. Polymer coating did not impact the strength of the hernia repair.

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Disruption of the Gut Microbiome: Clostridium difficile Infection and the Threat of Antibiotic Resistance

Cited by 88 publications

References 101 publications

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Genome Characterization of a Novel Binary Toxin-Positive Strain of <em>Clostridium difficile</em> and Comparison with the Epidemic 027 and 078 Strains

Bis‐Cyclic Guanidines as a Novel Class of Compounds Potent against Clostridium difficile

Infection prevention using affinity polymer-coated, synthetic meshes in a pig hernia model

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