{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:49:50Z","timestamp":1791906590814,"version":"4.3.4"},"reference-count":14,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T00:00:00Z","timestamp":1755475200000},"content-version":"vor","delay-in-days":47,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009139","name":"DZIF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009139","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006603","name":"BMBF","doi-asserted-by":"publisher","award":["01KA1702"],"award-info":[{"award-number":["01KA1702"]}],"id":[{"id":"10.13039\/501100006603","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>This first-in-human, single ascending dose study evaluated the safety, tolerability and pharmacokinetics (PK) of the decaprenylphosphoryl-\u03b2-D-ribose-2\u2032-epimerase (DprE1) inhibitor BTZ-043.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>BTZ-043 was administered as an oral suspension at doses of 125, 250 and 500\u2005mg along with placebo to healthy participants. Safety assessments included evaluation of laboratory parameters, vital signs, physical and neurological examination, and 12-lead ECG. Blood samples for PK assessment in plasma were collected over a 36 h post-dose period. PK parameters were calculated using non-compartmental analysis for parent BTZ-043, metabolites M1 and M2, and BTZ-043total (sum of BTZ-043 and M2) in plasma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Thirty participants completed the study. All administered BTZ-043 doses were safe and well tolerated. Nervous system disorders (dizziness and headache) and vascular disorders (hypertension and hot flush) were the most frequently reported adverse events (AEs). All AEs were mild or moderate. The parent compound BTZ-043 was rapidly metabolized to metabolite M2 (unknown activity), with median time to maximum concentration in plasma (tmax) of 1.5\u2005h (1\u20132\u2005h). BTZ-043 and M2 had a short half-life. The second main inactive metabolite M1 showed a median tmax of 7\u20138.5\u2005h and a geometric mean half-life of 8.4\u20139.0\u2005h. The increases in AUC and maximum concentration of drug in plasma (Cmax) of BTZ-043 were more than dose-proportional, and those of BTZ-043total were almost dose-proportional. No relevant differences in systemic exposures between males and females were observed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>BTZ-043 was safe, well tolerated and underwent rapid absorption, metabolism and elimination, supporting further clinical development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jacamr\/dlaf127","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T13:58:49Z","timestamp":1752501529000},"source":"Crossref","is-referenced-by-count":6,"title":["First-in-human study of the benzothiazinone and DprE1 inhibitor BTZ-043, a novel drug candidate for the treatment of Tuberculosis"],"prefix":"10.1093","volume":"7","author":[{"given":"Wandini","family":"Lutchmun","sequence":"first","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Heinrich","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital , Munich ,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Department of Immunology, Infection and Pandemic Research , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elin M","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Centre , Nijmegen ,","place":["the Netherlands"]},{"name":"Department of Pharmacy, Uppsala University , Uppsala ,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Kloss","sequence":"additional","affiliation":[{"name":"Transfer Group Anti-Infectives, Leibniz Institute for Natural Product Research and Infection Biology, Leibniz-HKI , Jena ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Konsten","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6625-9857","authenticated-orcid":false,"given":"Julia","family":"Dreisbach","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7642-1835","authenticated-orcid":false,"given":"Michael","family":"Hoelscher","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital , Munich ,","place":["Germany"]},{"name":"German Center for Infection Research (DZIF), Munich Partner Site , Munich ,","place":["Germany"]},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Department of Immunology, Infection and Pandemic Research , Munich ,","place":["Germany"]},{"name":"Unit Global Health, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (HMGU) , Neuherberg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"2025081808221090700_dlaf127-B1","author":"World Health Organization"},{"key":"2025081808221090700_dlaf127-B2","author":"WHO"},{"key":"2025081808221090700_dlaf127-B3","doi-asserted-by":"publisher","first-page":"2331","DOI":"10.1056\/NEJMoa2117166","article-title":"A 24-week, all-oral regimen for rifampin-resistant tuberculosis","volume":"387","author":"Nyang\u2019wa","year":"2022","journal-title":"N Engl J Med"},{"key":"2025081808221090700_dlaf127-B4","doi-asserted-by":"publisher","first-page":"9","DOI":"10.4103\/2212-5531.307132","article-title":"High frequency of bedaquiline resistance in programmatically treated drug-resistant TB patients with sustained culture-positivity in Cape Town, South Africa","volume":"9","author":"Derendinger","year":"2021","journal-title":"Int J Mycobacteriol"},{"key":"2025081808221090700_dlaf127-B5","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1126\/science.1171583","article-title":"Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis","volume":"324","author":"Makarov","year":"2009","journal-title":"Science"},{"key":"2025081808221090700_dlaf127-B6","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1016\/j.cmi.2024.06.016","article-title":"Candidate anti-tuberculosis medicines and regimens under clinical evaluation","volume":"30","author":"Hoelscher","year":"2024","journal-title":"Clin Microbiol Infect"},{"key":"2025081808221090700_dlaf127-B7","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1038\/s41467-025-56146-9","article-title":"The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis","volume":"16","author":"R\u00f6mpp","year":"2025","journal-title":"Nat Commun"},{"key":"2025081808221090700_dlaf127-B8","doi-asserted-by":"publisher","first-page":"e0059723","DOI":"10.1128\/aac.00597-23","article-title":"Drug distribution and efficacy of the DprE1 inhibitor BTZ-043 in the C3HeB\/FeJ mouse tuberculosis model","volume":"67","author":"Ramey","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"2025081808221090700_dlaf127-B9","doi-asserted-by":"publisher","first-page":"2187","DOI":"10.1002\/anie.201609737","article-title":"In vivo dearomatization of the potent antituberculosis agent BTZ043 via Meisenheimer complex formation","volume":"56","author":"Kloss","year":"2017","journal-title":"Angew Chem Int Ed Engl"},{"key":"2025081808221090700_dlaf127-B10","volume-title":"United States FDA Guidelines: Guidance for Industry, Bioanalytical Method Validation","author":"Food and Drug Administration","year":"2001"},{"key":"2025081808221090700_dlaf127-B11","author":"European Medicines Agency"},{"key":"2025081808221090700_dlaf127-B12","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1002\/psp4.12161","article-title":"Model evaluation of continuous data pharmacometric models: metrics and graphics","volume":"6","author":"Nguyen","year":"2017","journal-title":"CPT Pharmacometrics Syst Pharmacol"},{"key":"2025081808221090700_dlaf127-B13","doi-asserted-by":"publisher","first-page":"100952","DOI":"10.1016\/j.lanmic.2024.07.015","article-title":"Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043-02): an open-label, dose-expansion, randomised, controlled, phase 1b\/2a trial","volume":"6","author":"Heinrich","year":"2025","journal-title":"Lancet Microbe"},{"key":"2025081808221090700_dlaf127-B14","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1093\/jac\/dkaf076","article-title":"Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043","volume":"80","author":"Koele","year":"2025","journal-title":"J Antimicrob Chemother"}],"container-title":["JAC-Antimicrobial Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/7\/4\/dlaf127\/64076500\/dlaf127.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jacamr\/article-pdf\/7\/4\/dlaf127\/64076500\/dlaf127.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T12:22:16Z","timestamp":1755519736000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jacamr\/article\/doi\/10.1093\/jacamr\/dlaf127\/8237288"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,2]]},"references-count":14,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,7,2]]}},"URL":"https:\/\/doi.org\/10.1093\/jacamr\/dlaf127","relation":{},"ISSN":["2632-1823"],"issn-type":[{"value":"2632-1823","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,7,2]]},"article-number":"dlaf127"}}