Genetic Mechanisms of Vancomycin Resistance in Clostridioides difficile: A Systematic Review

Eubank, Taryn A; Gonzales-Luna, Anne J; Hurdle, Julian G.; Garey, Kevin W.

doi:10.3390/antibiotics11020258

Cited by 20 publications

(17 citation statements)

References 65 publications

(101 reference statements)

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“…The reason for the lack of vancomycin resistance in wild-type C. Instead, we have found that high expression of the vanG operon confers resistance to a low level of vancomycin (4 μg ml −1 ). Similar results have recently been obtained for C. difficile mutants isolated by serial passages in vitro in the presence of increasing concentrations of vancomycin and for several clinical isolates; however, all these strains contained additional mutations elsewhere in the chromosome (Eubank et al, 2022;Shen et al, 2020;Wickramage et al, 2021).…”

Section: Vancomycin Resistance and Vang Expressionsupporting

confidence: 85%

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VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Belitsky

2022

Molecular Microbiology

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A Clostridioides difficile strain deficient in the ddl gene is unable to synthesize the dipeptide D‐Ala‐D‐Ala, an essential component of peptidoglycan and the target of vancomycin. We isolated spontaneous suppressors of a ∆ddl mutation that allowed cell growth in the absence of D‐Ala‐D‐Ala. The mutations caused constitutive or partly constitutive expression of the vancomycin‐inducible vanG operon responsible for the synthesis of D‐Ala‐D‐Ser, which can replace D‐Ala‐D‐Ala in peptidoglycan. The mutations mapped to the vanS or vanR genes, which regulate expression of the vanG operon. The constitutive level of vanG expression was about 10‐fold above that obtained by vancomycin induction. The incorporation of D‐Ala‐D‐Ser into peptidoglycan due to high expression of the vanG operon conferred only low‐level resistance to vancomycin, but VanG was found to synthesize D‐Ala‐D‐Ala in addition to D‐Ala‐D‐Ser. However, the same, low resistance to vancomycin was also observed in cells completely unable to synthesize D‐Ala‐D‐Ala and grown in the presence of D‐Ala‐D‐Ser. D‐Ala‐D‐Ala presence was required for efficient vancomycin induction of the vanG operon showing that vancomycin is not by itself able to activate VanS. D‐Ala‐D‐Ser, similar to D‐Ala‐D‐Ala, served as an anti‐activator of DdlR, the positive regulator of the ddl gene, thereby coupling vanG and ddl expression.

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Section: Vancomycin Resistance and Vang Expressionsupporting

confidence: 85%

“…Additional mutations may be needed to achieve higher level of resistance to vancomycin. Indeed, such mutations in other C. difficile strains with the increased resistance to vancomycin have been described (Eubank et al, 2022; Leeds et al, 2014; Shen et al, 2020; Wickramage et al, 2021; Zhou et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Belitsky

2022

Molecular Microbiology

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“…As these Stickland reductases are cofactor-dependent, species-specific, and essential metabolic enzymes during disease, they have potential to be better pharmacological interventions in the age of antibiotic resistance. While vancomycin, fidaxomicin and metronidazole are standard antibiotic treatments for C. difficile , there is a high rate of infection reoccurrences and a high number of emerging hypervirulent strains resistant to standard care ( He et al, 2013 ; Eubank et al, 2022 ; Olaitan et al, 2022 ). In addition, these antibiotics don’t address the cause of infection—the imbalance of the microbiome—but rather combat the effects.…”

Section: Resultsmentioning

confidence: 99%

Characterizing metabolic drivers of Clostridioides difficile infection with activity-based hydrazine probes

Bustin

Abbas²,

Wang³

et al. 2023

Front. Pharmacol.

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Many enzymes require post-translational modifications or cofactor machinery for primary function. As these catalytically essential moieties are highly regulated, they act as dual sensors and chemical handles for context-dependent metabolic activity. Clostridioides difficile is a major nosocomial pathogen that infects the colon. Energy generating metabolism, particularly through amino acid Stickland fermentation, is central to colonization and persistence of this pathogen during infection. Here using activity-based protein profiling (ABPP), we revealed Stickland enzyme activity is a biomarker for C. difficile infection (CDI) and annotated two such cofactor-dependent Stickland reductases. We structurally characterized the cysteine-derived pyruvoyl cofactors of D-proline and glycine reductase in C. difficile cultures and showed through cofactor monitoring that their activity is regulated by their respective amino acid substrates. Proline reductase was consistently active in toxigenic C. difficile, confirming the enzyme to be a major metabolic driver of CDI. Further, activity-based hydrazine probes were shown to be active site-directed inhibitors of proline reductase. As such, this enzyme activity, via its druggable cofactor modality, is a promising therapeutic target that could allow for the repopulation of bacteria that compete with C. difficile for proline and therefore restore colonization resistance against C. difficile in the gut.

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“…Furthermore, there are reliable data on oral vancomycin, as it is widely used in Clostridioides difficile infections. Few antibiotic resistances to vancomycin occurred over time, with a treatment duration of 10 days or even longer ( 52 – 54 ). However, recent experimental data demonstrated a significant role of Enterococci species in the pathogenesis of AL ( 25 , 55 ).…”

Section: Discussionmentioning

confidence: 99%

Antibiotic Bowel Decontamination in Gastrointestinal Surgery—A Single-Center 20 Years’ Experience

Schardey

Ahnen

Schardey³

et al. 2022

Front. Surg.

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ObjectiveAnastomotic leakage, surgical site infections, and other infectious complications are still common complications in gastrointestinal surgery. The concept of perioperative antibiotic bowel decontamination demonstrates beneficial effects in single randomized controlled trials (RCTs), but data from routine clinical use are still sparse. Our aim was to analyze the data from the routine clinical use of perioperative antibiotic bowel decontamination in gastrointestinal surgery.MethodsBased on 20 years’ experience, we performed a retrospective analysis of all cases in oncologic gastrointestinal surgery with the use of antibiotic bowel decontamination in gastric, sigmoid, and rectal cancer. Clinical data and perioperative outcomes were analyzed, especially regarding anastomotic leakage, surgical site infections, and other infectious complications.ResultsA total of n = 477 cases of gastrointestinal surgery in gastric cancer (n = 80), sigmoid cancer (n = 168), and rectal cancer (n = 229) using a perioperative regimen of antibiotic bowel decontamination could be included in this analysis. Overall, anastomotic leakage occurred in 4.4% (2.5% gastric cancer, 3.0% sigmoid cancer, 6.1% rectal cancer) and surgical site infections in 9.6% (6.3% gastric cancer, 9.5% sigmoid cancer, 10.9% rectal cancer). The incidence of all infectious complications was 13.6% (12.5% gastric cancer, 11.3% sigmoid cancer, 15.7% rectal cancer). Mortality was low, with an overall rate of 1.1% (1.3% gastric cancer, 1.8% sigmoid cancer, 0.4% rectal cancer). Antibiotic decontamination was completed in 98.5%. No adverse effects of antibiotic bowel decontamination could be observed.ConclusionOverall, in this large cohort, we can report low rates of surgery-related serious morbidity and mortality when perioperative antibiotic bowel decontamination is performed. The rates are lower than other clinical reports. In our clinical experience, the use of perioperative antibiotic bowel decontamination appears to improve patient safety and surgical outcomes during gastrointestinal oncologic procedures in a routine clinical setting.

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Genetic Mechanisms of Vancomycin Resistance in Clostridioides difficile: A Systematic Review

Cited by 20 publications

References 65 publications

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

VanG‐ and D‐Ala‐D‐Ser‐dependent peptidoglycan synthesis and vancomycin resistance in Clostridioides difficile

Characterizing metabolic drivers of Clostridioides difficile infection with activity-based hydrazine probes

Antibiotic Bowel Decontamination in Gastrointestinal Surgery—A Single-Center 20 Years’ Experience

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