{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:24:37Z","timestamp":1791591877539,"version":"4.3.4"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011795","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000}}],"reference-count":65,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T00:00:00Z","timestamp":1753056000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI177619"],"award-info":[{"award-number":["R01AI177619"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P41GM135018"],"award-info":[{"award-number":["P41GM135018"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM038784"],"award-info":[{"award-number":["R01GM038784"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>Small-molecule screens can advance therapeutic discovery and uncover new features of pathogen biology. Through a luminescence-based screen, we identified clinically approved dihydropyridines that impaired fitness of the intracellular pathogen <jats:italic>Brucella ovis<\/jats:italic> in mammalian phagocytes. Given that dihydropyridines block mammalian L-type calcium channels, and based on our observation that drug treatment perturbed calcium and manganese levels in host phagocytes, we initially hypothesized a host-directed mechanism of action. However, dose-response assays in axenic medium showed that dihydropyridines have direct antimicrobial effects. To explore the genetic basis of dihydropyridine sensitivity, we selected for <jats:italic>B. ovis<\/jats:italic> mutants capable of growing in the presence of cilnidipine, a representative compound from this drug class. Cilnidipine-resistant mutants harbored single-nucleotide deletions in the <jats:italic>bepE<\/jats:italic> transporter pseudogene that restored its open reading frame, enabling expression of a functional RND-family transporter. <jats:italic>B. ovis<\/jats:italic> is a host-restricted ovine pathogen that has experienced significant pseudogenization in its recent evolutionary history. Reversion mutations that restored the open reading frame of the <jats:italic>bepE<\/jats:italic> pseudogene increased <jats:italic>B. ovis<\/jats:italic> resistance not only to dihydropyridines but also to a broad range of cell envelope-disrupting agents. Conversely, deleting <jats:italic>bepE<\/jats:italic> in <jats:italic>Brucella abortus<\/jats:italic>, a closely related zoonotic species that retains an intact version of the gene, increased its sensitivity to envelope disruptors <jats:italic>in vitro<\/jats:italic> and to cilnidipine in the intracellular niche. We conclude that <jats:italic>bepE<\/jats:italic> is a key determinant of chemical stress resistance in <jats:italic>Brucella<\/jats:italic> spp., and that its pseudogenization in <jats:italic>B. ovis<\/jats:italic> contributes to the documented hypersensitivity of this host-restricted lineage to chemical stressors.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011795","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T17:43:15Z","timestamp":1753119795000},"page":"e1011795","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reversion of a RND transporter pseudogene reveals latent stress resistance potential in Brucella 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