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Here, we report 5-carboxamide-substituted barbituric acid as a promising scaffold for developing new drugs against Mtb. Fenoxacrim, the initial hit compound identified through phenotypic screening, demonstrated potent activity against Mtb. It is active against drug-susceptible and multidrug-resistant clinical Mtb isolates as well as against intracellular Mtb in infected THP-1 derived macrophages. Fenoxacrim demonstrates high selectivity (&amp;gt;73-fold) for the pathogen over several tested mammalian cell lines. Other than Mtb, fenoxacrim exhibits strong bactericidal activity against several Gram-positive pathogens, including methicillin-resistantStaphylococcus aureus (MRSA), with in vitro potency comparable to, or exceeding several clinically used antibiotics. Medicinal chemistry optimization efforts yielded new fenoxacrim analogues with improved Mtb specificity, enhanced potency, and reduced cytotoxicity. Mode-of-action studies suggest that fenoxacrim inhibits undecaprenyl pyrophosphate synthase (UPPS) and dissipates the bacterial membrane potential. Together, these findings highlight the potential of 5-carboxamidebarbituric acid derivatives as a foundation for developing new antibacterial agents with novel modes of action for the treatment of tuberculosis and other drug-resistant bacterial infections.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00420","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:01:52Z","timestamp":1786982512000},"page":"3191-3203","source":"Crossref","is-referenced-by-count":0,"title":["5-Carboxamide-Substituted\nBarbituric Acids:\nPromising Scaffolds for Drug Development against\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7206-0685","authenticated-orcid":true,"given":"Henok A.","family":"Sahile","sequence":"first","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2636-510X","authenticated-orcid":true,"given":"Bhuwan","family":"Awasthi","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2405 Wesbrook Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9047-6896","authenticated-orcid":true,"given":"Jonas E.","family":"Olsen","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2405 Wesbrook Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houria","family":"Afshar","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung-Won","family":"Kim","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2405 Wesbrook Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itay","family":"Amrom","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1065-9653","authenticated-orcid":true,"given":"Zohra","family":"Nikjo","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0049-5408","authenticated-orcid":true,"given":"Leah","family":"Rankine-Wilson","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wayne W. H.","family":"Law","sequence":"additional","affiliation":[{"name":"University of Toronto , , 686 Bay Street, Rm. 20-9705 , ,","place":["Toronto, Canada, M5G 0A4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selvarani","family":"Vimalanathan","sequence":"additional","affiliation":[{"name":"University of British Columbia , , 2350 Health Sciences Mall , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement K.M.","family":"Tsui","sequence":"additional","affiliation":[{"name":"National Centre for Infectious Diseases , , ,","place":["Singapore, Singapore, 308442"]},{"name":"University of British Columbia , , ,","place":["Vancouver, Canada, V6T 1Z3"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-2209","authenticated-orcid":true,"given":"John L.","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"University of Toronto , , 686 Bay Street, Rm. 20-9705 , ,","place":["Toronto, Canada, M5G 0A4"]},{"name":"The University of Toronto , , 1 King\u2019s College Circle Room 5207 , ,","place":["Toronto, Canada, M5S 1A8"]},{"name":"The University of Toronto , , 101 College St Suite 15-701 , ,","place":["Toronto, Canada, M5G 2C4"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2101-1329","authenticated-orcid":true,"given":"Brent D. 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P.\n          \n          Methods for reducing\nuric acid levels using barbiturate derivative; WO 2,015,073,317\nA1, 2013."},{"issue":"23","key":"2026091109092717400_cit18","doi-asserted-by":"publisher","first-page":"6183","DOI":"10.1016\/j.bmc.2016.09.074","article-title":"Synthesis of N-aryl and N-arylcarbamoylamino\nderivatives of 1,3-diazinane-5-carboxamide and their activity against\nglioblastoma LN-229 cell line","volume":"24","author":"Hron","year":"2016","journal-title":"Bioorg. Med.\nChem."},{"key":"2026091109092717400_cit19","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1039\/C2SC21713A","article-title":"Natural\nproduct inspired antibacterial tetramic acid libraries with dual enzyme\ninhibition","volume":"4","author":"Jeong","year":"2013","journal-title":"Chem. 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