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This pathogen often takes advantage of microbial dysbiosis provoked by antibiotic use. With the increasing incidence and severity of infections, coupled with high recurrence rates, there is an urgent need to identify innovative therapies that can preserve the healthy state of the gut microbiota. In this study, we screened a microbial metabolite library against\n                      <jats:italic>C. difficile<\/jats:italic>\n                      . From a collection of 527 metabolites, we identified 18 compounds with no previously identified antimicrobial activity and metabolites that exhibited potent activity against\n                      <jats:italic>C. difficile<\/jats:italic>\n                      growth. Of these 18 hits, five drugs and three metabolites displayed the most potent anti-\n                      <jats:italic>C<\/jats:italic>\n                      .\n                      <jats:italic>difficile<\/jats:italic>\n                      activity and were subsequently assessed against 20 clinical isolates of\n                      <jats:italic>C. difficile<\/jats:italic>\n                      . These potent agents included ecteinascidin 770 (minimum inhibitory concentration against 50% of isolates [MIC\n                      <jats:sub>50<\/jats:sub>\n                      ] \u22640.06 \u00b5g\/mL); 8-hydroxyquinoline derivatives, such as broxyquinoline and choloroquinaldol (MIC\n                      <jats:sub>50<\/jats:sub>\n                      = 0.125 \u00b5g\/mL); ionomycin calcium salt, carbadox, and robenidine hydrochloride (MIC\n                      <jats:sub>50<\/jats:sub>\n                      = 1 \u00b5g\/mL); and dronedarone and milbemycin oxime (MIC\n                      <jats:sub>50<\/jats:sub>\n                      = 4 \u00b5g\/mL). Unlike vancomycin and fidaxomicin, which are the standard-of-care anti-\n                      <jats:italic>C<\/jats:italic>\n                      .\n                      <jats:italic>difficile<\/jats:italic>\n                      antibiotics, most of these metabolites showed robust bactericidal activity within 2\u20138 h with minimal impact on the growth of representative members of the normal gut microbiota. These results suggest that the drugs and microbial metabolite scaffolds may offer alternative avenues to address unmet needs in\n                      <jats:italic>C. difficile<\/jats:italic>\n                      disease prevention and treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      The most frequent infection associated with hospital settings is\n                      <jats:italic>Clostridioides difficile<\/jats:italic>\n                      , which can cause fatal diarrhea and severe colitis, toxic megacolon, sepsis, and leaky gut. Those who have taken antibiotics for other illnesses that affect the gut's healthy microbiota are more susceptible to\n                      <jats:italic>C. difficile<\/jats:italic>\n                      infection (CDI). Recently, some reports showed higher recurrence rates and resistance to anti-\n                      <jats:italic>C. difficile<\/jats:italic>\n                      , which may compromise the efficacy of CDI treatment. Our study is significant because it is anticipated to discover novel microbial metabolites and drugs with microbial origins that are safe for the intestinal flora, effective against\n                      <jats:italic>C. difficile<\/jats:italic>\n                      , and reduce the risk of recurrence associated with CDI.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/msphere.00273-24","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T08:43:36Z","timestamp":1719564216000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":11,"title":["Exploring novel microbial metabolites and drugs for inhibiting\n                    <i>Clostridioides difficile<\/i>"],"prefix":"10.1128","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9937-742X","authenticated-orcid":false,"given":"Ahmed A.","family":"Abouelkhair","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"},{"name":"Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"},{"name":"Department of Bacteriology, Mycology, and Immunology, Faculty of Veterinary Medicine, University of Sadat City, Sadat City, Menoufia, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0939-0458","authenticated-orcid":true,"given":"Mohamed N.","family":"Seleem","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"},{"name":"Center for One Health Research, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1403772"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2478"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)02185-7"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis335"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1408913"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.15620\/cdc:82532"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1086\/521859"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1086\/422002"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.39029"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.7861\/clinmedicine.18-3-237"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26580-6"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit147"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2016.11.006"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4161\/gmic.1.4.12706"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI72336"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1177\/1756284821994736"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2013.04.045"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-023-00933-y"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix1085"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00090-08"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2019.00099"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.20"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2012.01.004"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2010.485614"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis495"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/934594"},{"key":"e_1_3_3_28_2","first-page":"278","article-title":"Fidaxomicin (Dificid), a novel oral macrocyclic antibacterial agent for the treatment of Clostridium difficile-associated diarrhea in adults","volume":"37","author":"Cruz MP","year":"2012","unstructured":"Cruz MP. 2012. 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