{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T07:41:49Z","timestamp":1777362109901,"version":"3.51.4"},"posted":{"date-parts":[[2025,9,24]]},"group-title":"Microbiology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,24]],"date-time":"2025-09-24T00:00:00Z","timestamp":1758672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["AI143784"],"award-info":[{"award-number":["AI143784"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cancer Center Support Grant","award":["CA-77598"],"award-info":[{"award-number":["CA-77598"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,24]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Conditionally essential pathways - such as the biotin biosynthesis - represent promising targets for new antibiotics. However, the chemical interrogation of the biotin pathway with an orally effective lead remains elusive, and the preclinical development of biotin inhibitors for mycobacterial infections in vivo is challenging due to the unusually high concentration of biotin in standard mouse models. Structure-guided optimization was applied to develop the first oral lead targeting aminotransferase BioA, a key enzyme in bacterial biotin biosynthesis, resulting in\n                  <jats:bold>C48<\/jats:bold>\n                  , a picomolar inhibitor displaying sub-micromolar MICs against\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  (Mtb). Mechanism of action was confirmed by biochemical, structural, and genetic studies.\n                  <jats:bold>C48<\/jats:bold>\n                  demonstrated favorable pharmacokinetics and excellent oral bioavailability resulting in over 39,000-fold improved exposure. We next developed an easy-to-operate, low-biotin mouse model that recapitulates human biotin physiology.\n                  <jats:bold>C48<\/jats:bold>\n                  significantly reduced Mtb burden in this low-biotin mouse model, providing the first in vivo proof-of-concept for targeting biotin biosynthesis in Mtb.\n                <\/jats:p>","DOI":"10.1101\/2025.09.24.678246","type":"posted-content","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T05:05:16Z","timestamp":1758776716000},"source":"Crossref","is-referenced-by-count":2,"title":["Validating Conditionally Essential Targets: Discovery of the First Orally Effective Biotin Inhibitor against\n                  <i>Mycobacterium Tuberculosis<\/i>"],"prefix":"10.64898","author":[{"given":"Qiang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua B.","family":"Wallach","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York 10021, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yahani P.","family":"Jayasinghe","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5765-0459","authenticated-orcid":false,"given":"Mark R.","family":"Sullivan","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Disease, Harvard T.H. 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