{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:54:06Z","timestamp":1772412846010,"version":"3.50.1"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the Sichuan Province Distinguished Young Science and Technology Program","award":["2019JD100008"],"award-info":[{"award-number":["2019JD100008"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Biomed"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We developed JBD0131, a novel nitroimidazooxazole antitubercular agent, and conducted a comprehensive preclinical evaluation of its safety pharmacology, toxicology, and pharmacokinetics in SD rats and Beagle dogs. JBD0131 was well-tolerated in repeated-dose oral studies, with no treatment-related mortality or significant alterations in organ weights or significant alterations in organ-to-body weight ratios observed. The no-observed-adverse-effect level (NOAEL) was established at 480\u00a0mg\/kg\/day in rats and 300\u00a0mg\/kg\/day in female dogs. In male dogs, the NOAEL was determined to be 15\u00a0mg\/kg\/day, a discrepancy primarily attributed to a slight trend toward Corrected QT interval (QTc) prolongation at higher doses (60 and 300\u00a0mg\/kg\/day) to which males exhibited greater cardiovascular sensitivity. Pharmacokinetic analysis revealed dose-proportional systemic exposure with no accumulation of JBD0131. Although the metabolite DM131 showed moderate accumulation, it was identified as the amino-reduction detoxification product of JBD0131, a conversion that yields a more stable species and is supported by favorable clinical safety data. While Phase I clinical trials of JBD0131 have been reported, this preclinical study remains indispensable as it establishes the toxicological \"ceiling\" and defines safety margins through supra-therapeutic dosing. By identifying sex-specific sensitivities and clarifying metabolite safety, this work provides a critical scientific foundation for long-term clinical monitoring and risk assessment. Based on indirect comparisons with reported historical data for clinical agents such as bedaquiline and pretomanid, JBD0131 demonstrated a favorable preclinical safety profile in the models tested, supporting its continued development for multidrug-resistant tuberculosis.<\/jats:p>","DOI":"10.1186\/s43556-026-00414-7","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:01:15Z","timestamp":1772409675000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Safety pharmacology and toxicology of a novel nitroimidazooxazole antitubercular agent in SD rat and Beagle dogs"],"prefix":"10.1186","volume":"7","author":[{"given":"Dandan","family":"Peng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Furong","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minyang","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ning","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manni","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenling","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6513-6422","authenticated-orcid":false,"given":"Xiawei","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"414_CR1","unstructured":"WHO. Global tuberculosis report 2023. https:\/\/www.who.int\/publications\/i\/item\/9789240083851. 2023. Accessed 08 Sept July 2025."},{"key":"414_CR2","unstructured":"WHO. Tuberculosis. https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/tuberculosis. 2025. Accessed 14 Mar 2025."},{"key":"414_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2025.101265","volume":"82","author":"X Wang","year":"2025","unstructured":"Wang X, Shang A, Chen H, Li J, Jiang Y, Wang L, et al. Global, regional, and national disease burden of multidrug-resistant tuberculosis without extensive drug resistance, 1990\u20132021: findings from the Global Burden of Disease Study 2021. Drug Resist Updat. 2025;82:101265. https:\/\/doi.org\/10.1016\/j.drup.2025.101265.","journal-title":"Drug Resist Updat"},{"issue":"3","key":"414_CR4","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.cmi.2016.10.008","volume":"23","author":"K Dheda","year":"2017","unstructured":"Dheda K, Chang KC, Guglielmetti L, Furin J, Schaaf HS, Chesov D, et al. Clinical management of adults and children with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Microbiol Infect. 2017;23(3):131\u201340. https:\/\/doi.org\/10.1016\/j.cmi.2016.10.008.","journal-title":"Clin Microbiol Infect"},{"issue":"6","key":"414_CR5","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1164\/rccm.202009-3527OC","volume":"204","author":"M Roelens","year":"2021","unstructured":"Roelens M, Battista Migliori G, Rozanova L, Estill J, Campbell JR, Cegielski JP, et al. Evidence-based definition for extensively drug-resistant tuberculosis. Am J Respir Crit Care Med. 2021;204(6):713\u201322. https:\/\/doi.org\/10.1164\/rccm.202009-3527OC.","journal-title":"Am J Respir Crit Care Med"},{"key":"414_CR6","doi-asserted-by":"publisher","unstructured":"Alsayed SSR, Gunosewoyo H. Tuberculosis: Pathogenesis, Current Treatment Regimens and New Drug Targets. Int J Mol Sci. 2023;24(6). https:\/\/doi.org\/10.3390\/ijms24065202","DOI":"10.3390\/ijms24065202"},{"issue":"10","key":"414_CR7","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1056\/NEJMoa1901814","volume":"382","author":"F Conradie","year":"2020","unstructured":"Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, et al. Treatment of highly drug-resistant pulmonary tuberculosis. N Engl J Med. 2020;382(10):893\u2013902. https:\/\/doi.org\/10.1056\/NEJMoa1901814.","journal-title":"N Engl J Med"},{"issue":"39","key":"414_CR8","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202400176","volume":"11","author":"MY Yan","year":"2024","unstructured":"Yan MY, Li H, Qu YM, Li SS, Zheng D, Guo XP, et al. CRISPR screening and comparative LC-MS analysis identify genes mediating efficacy of delamanid and pretomanid against Mycobacterium tuberculosis. Adv Sci. 2024;11(39):e2400176. https:\/\/doi.org\/10.1002\/advs.202400176.","journal-title":"Adv Sci"},{"issue":"8","key":"414_CR9","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-058606","volume":"12","author":"C Padmapriyadarsini","year":"2022","unstructured":"Padmapriyadarsini C, Devaleenal B, Ponnuraja C, Ramraj B, Singla R, Parmar M, et al. Randomised trial to evaluate the effectiveness and safety of varying doses of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant or treatment intolerant\/non-responsive multidrug-resistant pulmonary tuberculosis: study protocol. BMJ Open. 2022;12(8):e058606. https:\/\/doi.org\/10.1136\/bmjopen-2021-058606.","journal-title":"BMJ Open"},{"issue":"9","key":"414_CR10","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1016\/s2213-2600(25)00194-8","volume":"13","author":"L Guglielmetti","year":"2025","unstructured":"Guglielmetti L, Khan U, Vel\u00e1squez GE, Gouillou M, Ali MH, Amjad S, et al. Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial. Lancet Respir Med. 2025;13(9):809\u201320. https:\/\/doi.org\/10.1016\/s2213-2600(25)00194-8.","journal-title":"Lancet Respir Med"},{"issue":"12","key":"414_CR11","doi-asserted-by":"publisher","first-page":"3252","DOI":"10.1093\/cid\/ciaa755","volume":"71","author":"TVA Nguyen","year":"2020","unstructured":"Nguyen TVA, Anthony RM, Cao TTH, Ba\u00f1uls AL, Nguyen VAT, Vu DH, et al. Delamanid resistance: update and clinical management. Clin Infect Dis. 2020;71(12):3252\u20139. https:\/\/doi.org\/10.1093\/cid\/ciaa755.","journal-title":"Clin Infect Dis"},{"key":"414_CR12","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.toxrep.2022.04.021","volume":"9","author":"R Bruning-Barry","year":"2022","unstructured":"Bruning-Barry R, Ambroso JL, Dillberger J, Yang TJ. Toxicity and toxicokinetic assessment of an anti-tubercular drug pretomanid in cynomolgus monkeys. Toxicol Rep. 2022;9:927\u201336. https:\/\/doi.org\/10.1016\/j.toxrep.2022.04.021.","journal-title":"Toxicol Rep"},{"issue":"17","key":"414_CR13","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1016\/j.bmcl.2019.06.055","volume":"29","author":"X Tao","year":"2019","unstructured":"Tao X, Gao C, Huang ZG, Luo W, Liu KL, Peng CT, et al. Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents. Bioorg Med Chem Lett. 2019;29(17):2511\u20135. https:\/\/doi.org\/10.1016\/j.bmcl.2019.06.055.","journal-title":"Bioorg Med Chem Lett"},{"key":"414_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2022.128871","volume":"72","author":"W Luo","year":"2022","unstructured":"Luo W, Huang Z, Xu D, Yang M, Zhu Y, Shen L, et al. Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent. Bioorg Med Chem Lett. 2022;72:128871. https:\/\/doi.org\/10.1016\/j.bmcl.2022.128871.","journal-title":"Bioorg Med Chem Lett"},{"issue":"12","key":"414_CR15","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70510","volume":"6","author":"J Miao","year":"2025","unstructured":"Miao J, Wang Z, Ding Z, Shi H, Qin Y, Gao T, et al. Safety, tolerability, and pharmacokinetics of a novel nitroimidazooxazole antitubercular agent in healthy adults: a phase I trial. MedComm (2020). 2025;6(12):e70510. https:\/\/doi.org\/10.1002\/mco2.70510.","journal-title":"MedComm (2020)"},{"issue":"1","key":"414_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02517-z","volume":"10","author":"N Chu","year":"2025","unstructured":"Chu N, Nie W, Du J, Wang M, Ma L, Wang Q, et al. A novel antituberculosis agent exhibits potent clinical efficacy and good safety profile: an open-label, randomized-controlled, multicenter, phase 2a trial. Signal Transduct Target Ther. 2025;10(1):427. https:\/\/doi.org\/10.1038\/s41392-025-02517-z.","journal-title":"Signal Transduct Target Ther"},{"issue":"23-24","key":"414_CR17","doi-asserted-by":"publisher","first-page":"1229","DOI":"10.1080\/17576180.2024.2404311","volume":"16","author":"T Gao","year":"2024","unstructured":"Gao T, Ou X, Miao J, Qin Y. Quantification of MDR-TB drug JBD0131 and its metabolite in plasma via UPLC-MS\/MS: application in first-in-human study. Bioanalysis. 2024;16(23\u201324):1229\u201340. https:\/\/doi.org\/10.1080\/17576180.2024.2404311.","journal-title":"Bioanalysis"},{"issue":"12","key":"414_CR18","doi-asserted-by":"publisher","DOI":"10.1016\/s2666-5247(24)00149-6","volume":"5","author":"ES Shaw","year":"2024","unstructured":"Shaw ES, Stoker NG, Potter JL, Claassen H, Leslie A, Tweed CD, et al. Bedaquiline: what might the future hold? Lancet Microbe. 2024;5(12):100909. https:\/\/doi.org\/10.1016\/s2666-5247(24)00149-6.","journal-title":"Lancet Microbe"},{"issue":"16","key":"414_CR19","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1007\/s40265-019-01207-9","volume":"79","author":"SJ Keam","year":"2019","unstructured":"Keam SJ. Pretomanid: first approval. Drugs. 2019;79(16):1797\u2013803. https:\/\/doi.org\/10.1007\/s40265-019-01207-9.","journal-title":"Drugs"},{"issue":"9","key":"414_CR20","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1056\/NEJMoa2119430","volume":"387","author":"F Conradie","year":"2022","unstructured":"Conradie F, Bagdasaryan TR, Borisov S, Howell P, Mikiashvili L, Ngubane N, et al. Bedaquiline-Pretomanid-Linezolid regimens for drug-resistant tuberculosis. N Engl J Med. 2022;387(9):810\u201323. https:\/\/doi.org\/10.1056\/NEJMoa2119430.","journal-title":"N Engl J Med"}],"container-title":["Molecular Biomedicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00414-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43556-026-00414-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43556-026-00414-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:01:16Z","timestamp":1772409676000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s43556-026-00414-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["414"],"URL":"https:\/\/doi.org\/10.1186\/s43556-026-00414-7","relation":{},"ISSN":["2662-8651"],"issn-type":[{"value":"2662-8651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]},"assertion":[{"value":"20 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 March 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted at Chengdu Huaxi Haichi Pharmaceutical Technology Co., Ltd. (Chengdu, China) in strict accordance with the approved study protocol, institutional standard operating procedures, and relevant animal welfare regulations. All procedures complied with the Principles of Good Laboratory Practice (GLP) as defined by the CFDA (2003), FDA (21 CFR Part 58), and OECD (ENV\/MC\/CHEM(98)17). The facility is GLP-certified by both the National Medical Products Administration (NMPA, formerly CFDA) and OECD, and is fully accredited by the AAALAC International. All animal experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the facility (Approval No.: IACUC-A2017007).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Jumbo Drug Bank Co. Ltd. provided the financial support to this preclinical trial. Ning Jiang and Xiawei Wei are employees of this Company and declare a potential conflict of interest. The other authors have no conflicts of interest to declare.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18"}}