p-Cresol Inhibitors Point to New Therapeutics for Treatment of Clostridioides difficile

Para-cresol production inhibitors show promise in leading to beneficial therapeutics that could help to restore colonization resistance, which could lead to a decrease in the likelihood of Clostridioides difficile infection (CDI) relapse, according to the results of a study published in Scientific Reports.¹

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Patients who experience CDI are at higher risk of relapse, with 35% of patients contracting CDI again. Fecal microbial transplant can successfully treat refractory CDI, but the treatment is expensive and there are safety concerns regarding its use.¹

Typically, the healthy gut microbiome provides resistance against CDI, but antibiotic usage can disrupt that, allowing for an infection to establish, according to the study.¹

p-cresol gets produced by para-Hydroxyphenylacetic (p-HPA) by the HpdBCA enzyme complex.¹

Investigators of the study identified potential ways to inhibit the HpdBCA decarboxylase, which can reduce the production of p-cresol and make CDI more susceptible to bacteria in the gut microbiome.¹

They reported that 4-Hydroxyphenylacetamide, previously identified as an inhibitor of HpdBCA decarboxylase, only reduced p-cresol production by 54.9 ± 13.5% compared with 4-Hydroxyphenylacetonitrile, which reduced it by 99.0 ± 0.4%.¹

Investigators also used a competition-index method to determine the inhibitors of p-cresol production, which yielded similar results.¹

Investigators found that p-HPA supplementation increased the C difficile 630∆erm compared to Escherichia coli in the assays. When p-HPA was not included, investigators found that C difficile 630∆erm was comprised of 18.1± 9.1%, but when 1.5mg/ml of p-cresol was presented, it increased to 87.5 ± 7.6%.¹

Investigators stated that it is important for the restoration of colonization resistance to occur in order to have effective treatment of C difficile. Further improvements on the treatment of CDI are needed, particularly therapies that work specifically against C difficile, according to the investigators.¹

According to the CDC, there were approximately 101.3 cases of CDI per 100,000 individuals, with a slightly higher incidence of community-associated cases at 51.2 cases per 100,000 individuals compared with health care-associated cases at 50.1 per 100,000 individuals in 2020.²

Additionally, investigators reported that the incidence rate of CDI increased with age with a higher prevalence in women and individuals who were White. Antibiotic use in the prior 12 weeks was reported in 61% of CDI cases, according to the CDC.¹

CDI recurrence occurs with a positive C difficile stool sample between 2 to 8 weeks after the last positive specimen was reported.³

The results of the surveillance were similar to the data from pre-pandemic years, despise significant delays in surveillance and investigation.²

The surveillance program is conducted through the Emerging Infections Program Healthcare-Associated Infections Community Interface of the CDC. The program’s aim is to identify insight for further public health research, including risk factors, vaccines, and prevention strategies.³

Reference

1. Harrison MA, Farthing RJ, Allen N, Ahern LM, et al. Identification of novel p-cresol inhibitors that reduce Clostridioides difficile's ability to compete with species of the gut microbiome. Sci Rep. 2023;13(1):9492. doi:10.1038/s41598-023-32656-8
2. Centers for Disease Control and Prevention. Emerging infections program, healthcare-associated infections ­– community interface surveillance report, Clostridioides difficile (CDI), 2020. Updated February 2, 2023. Accessed June 26, 2023. https://www.cdc.gov/hai/eip/Annual-CDI-Report-2020.html
3. Centers for Disease Control and Prevention. Clostridioides difficile infection (CDI) tracking. Updated February 24, 2022. Accessed June 26, 2023. https://www.cdc.gov/hai/eip/cdiff-tracking.html