{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T02:36:49Z","timestamp":1793241409904,"version":"4.5.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T00:00:00Z","timestamp":1635465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100020643","name":"Medical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020643","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020643","name":"Medical Research Centre","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020643","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p><jats:italic>Clostridioides difficile<\/jats:italic> is the leading cause of antibiotic-associated diarrhea and is capable of causing severe symptoms, such as pseudomembranous colitis and toxic megacolon. An unusual feature of <jats:italic>C. difficile<\/jats:italic> is the distinctive production of high levels of the antimicrobial compound <jats:italic>para<\/jats:italic>-cresol. <jats:italic>p<\/jats:italic>-Cresol production provides <jats:italic>C. difficile<\/jats:italic> with a competitive colonization advantage over gut commensal species, in particular, Gram-negative species. <jats:italic>p<\/jats:italic>-Cresol is produced by the conversion of <jats:italic>para<\/jats:italic>-hydroxyphenylacetic acid (<jats:italic>p<\/jats:italic>-HPA) <jats:italic>via<\/jats:italic> the actions of HpdBCA decarboxylase coded by the <jats:italic>hpdBCA<\/jats:italic> operon. Host cells and certain bacterial species produce <jats:italic>p<\/jats:italic>-HPA; however, the effects of <jats:italic>p<\/jats:italic>-HPA on the viability of <jats:italic>C. difficile<\/jats:italic> and other gut microbiota are unknown. Here we show that representative strains from all five <jats:italic>C. difficile<\/jats:italic> clades are able to produce <jats:italic>p<\/jats:italic>-cresol by two distinct mechanisms: (i) <jats:italic>via<\/jats:italic> fermentation of <jats:italic>p<\/jats:italic>-tyrosine and (ii) <jats:italic>via<\/jats:italic> uptake and turnover of exogenous <jats:italic>p<\/jats:italic>-HPA. We observed strain-specific differences in <jats:italic>p<\/jats:italic>-cresol production, resulting from differential efficiency of <jats:italic>p-<\/jats:italic>tyrosine fermentation; representatives of clade 3 (CD305) and clade 5 (M120) produced the highest levels of <jats:italic>p<\/jats:italic>-cresol <jats:italic>via<\/jats:italic> tyrosine metabolism, whereas the toxin A-\/B+ isolate from clade 4 (M68) produced the lowest level of <jats:italic>p<\/jats:italic>-cresol. All five lineages share at least 97.3% homology across the <jats:italic>hpdBCA<\/jats:italic> operon, responsible for decarboxylation of <jats:italic>p<\/jats:italic>-HPA to <jats:italic>p<\/jats:italic>-cresol, suggesting that the limiting step in <jats:italic>p<\/jats:italic>-cresol production may result from tyrosine to <jats:italic>p<\/jats:italic>-HPA conversion. We identified that elevated intracellular <jats:italic>p<\/jats:italic>-HPA, modulated indirectly <jats:italic>via<\/jats:italic> CodY, controls <jats:italic>p<\/jats:italic>-cresol production <jats:italic>via<\/jats:italic> inducing the expression of HpdBCA decarboxylase ubiquitously in <jats:italic>C. difficile<\/jats:italic> populations. Efficient turnover of <jats:italic>p<\/jats:italic>-HPA is advantageous to <jats:italic>C. difficile<\/jats:italic> as <jats:italic>p<\/jats:italic>-HPA has a deleterious effect on the growth of <jats:italic>C. difficile<\/jats:italic> and other representative Gram-negative gut bacteria, transduced potentially by the disruption of membrane permeability and release of intracellular phosphate. This study provides insights into the importance of HpdBCA decarboxylase in <jats:italic>C. difficile<\/jats:italic> pathogenesis, both in terms of <jats:italic>p<\/jats:italic>-cresol production and detoxification of <jats:italic>p<\/jats:italic>-HPA, highlighting its importance to cell survival and as a highly specific therapeutic target for the inhibition of <jats:italic>p<\/jats:italic>-cresol production across <jats:italic>C. difficile<\/jats:italic> species.<\/jats:p>","DOI":"10.3389\/fcimb.2021.757599","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T13:56:07Z","timestamp":1635515767000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Production of p-cresol by Decarboxylation of p-HPA by All Five Lineages of Clostridioides difficile Provides a Growth Advantage"],"prefix":"10.3389","volume":"11","author":[{"given":"Mark A.","family":"Harrison","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harparkash","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan W.","family":"Wren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa F.","family":"Dawson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1128\/JCM.01964-07","article-title":"Increased Sporulation Rate of Epidemic Clostridium Difficile Type 027\/Nap1","volume":"46","author":"Akerlund","year":"2008","journal-title":"J. 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