{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T01:23:31Z","timestamp":1792027411190,"version":"4.4.0"},"reference-count":32,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T00:00:00Z","timestamp":1647561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI-018045"],"award-info":[{"award-number":["AI-018045"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vanda Pharmaceuticals (United States)","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Vibrio cholerae uses cholera toxin (CT) to cause cholera, a severe diarrheal disease in humans that can lead to death within hours of the onset of symptoms. The catalytic activity of CT in target epithelial cells increases cellular levels of 3\u2032,5\u2032-cyclic AMP (cAMP), leading to the activation of the cystic fibrosis transmembrane conductance regulator (CFTR), an apical ion channel that transports chloride out of epithelial cells, resulting in an electrolyte imbalance in the intestinal lumen and massive water loss. Here we report that when administered perorally, benzopyrimido-pyrrolo-oxazinedione, (R)-BPO-27), a potent small molecule inhibitor of CFTR, blocked disease symptoms in a mouse model for acute diarrhea caused by toxigenic V. cholerae. We show that both (R)-BPO-27 and its racemic mixture, (R\/S)-BPO-27, are able to protect mice from CT-dependent diarrheal disease and death. Furthermore, we show that, consistent with the ability of the compound to block the secretory diarrhea induced by CT, BPO-27 has a measurable effect on suppressing the gut replication and survival of V. cholerae, including a 2010 isolate from Haiti that is representative of the most predominant \u2018variant strains\u2019 that are causing epidemic and pandemic cholera worldwide. Our results suggest that BPO-27 should advance to human Phase I studies that could further address its safety and efficacy as therapeutic or preventative drug intervention for diarrheal syndromes, including cholera, that are mediated by CFTR channel activation.<\/jats:p>","DOI":"10.3390\/toxins14030225","type":"journal-article","created":{"date-parts":[[2022,3,20]],"date-time":"2022-03-20T21:37:17Z","timestamp":1647812237000},"page":"225","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A Potent Inhibitor of the Cystic Fibrosis Transmembrane Conductance Regulator Blocks Disease and Morbidity Due to Toxigenic Vibrio cholerae"],"prefix":"10.3390","volume":"14","author":[{"given":"Fabian","family":"Rivera-Ch\u00e1vez","sequence":"first","affiliation":[{"name":"Division of Host-Microbe Systems and Therapeutics, Department of Pediatrics, University of California, San Diego, CA 92093, USA"},{"name":"Division of Biological Sciences, University of California, San Diego, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley T.","family":"Meader","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sinan","family":"Akosman","sequence":"additional","affiliation":[{"name":"Vanda Pharmaceuticals, Inc., Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vuk","family":"Koprivica","sequence":"additional","affiliation":[{"name":"Vanda Pharmaceuticals, Inc., Washington, DC 20037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Mekalanos","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2466","DOI":"10.1016\/S0140-6736(12)60436-X","article-title":"Cholera","volume":"379","author":"Harris","year":"2012","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sur, D., Kanungo, S., Sah, B., Manna, B., Ali, M., Paisley, A.M., Niyogi, S.K., Park, J.K., Sarkar, B., and Puri, M.K. 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