{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T13:52:56Z","timestamp":1791553976650,"version":"4.3.4"},"reference-count":51,"publisher":"American Chemical Society (ACS)","issue":"10","license":[{"start":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:00:00Z","timestamp":1789171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004328","name":"Genentech","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004328","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mycobacterium tuberculosis (Mtb) is responsible for more deaths per year than any other infectious disease. Resistance of circulating Mtb to the standard of care treatment regimen is an urgent global health crisis for which novel antibiotic treatments are needed. We have developed extremely potent, orally bioavailable, small-molecule inhibitors of inosine 5\u2032-monophosphate dehydrogenase (GuaB) that catalyze the rate-limiting step in de novo guanine biosynthesis. The inhibitors exhibited bactericidal activity against Mtb in extracellular, intracellular, and hypoxic environments that capture features of advanced disease pathology in patients. Mtb GuaB2 inhibitors (GuaBi) were efficacious in three different in vivo mouse models of Mtb lung infection: the C57BL\/6 super acute, C57BL\/6 chronic, and C3HeB\/FeJ (Kramnik) models. In the chronic BALB\/c infection model of primarily intracellular Mtb, no benefit was observed, whereas in the C3HeB\/FeJ model, a bedaquiline, pretomanid, and moxifloxacin treatment regimen that included GuaBi led to a rapid elimination of culturable Mtb infection in half of the mice. Notably, the C3HeB\/FeJ model recapitulates advanced pathophysiology and heterogeneous disease that includes caseous necrotic granulomas, intracellular and extracellular reservoirs of Mtb, and lethal progressive infection. These results support further evaluation of a GuaBi-containing therapeutic regimen in relapse-capable preclinical models.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00350","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T19:01:45Z","timestamp":1789239705000},"page":"3373-3384","source":"Crossref","is-referenced-by-count":0,"title":["Development\nof GuaB Inhibitors to Treat\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Infection"],"prefix":"10.1021","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1779-4914","authenticated-orcid":true,"given":"Eric M.","family":"Kofoed","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4663-4116","authenticated-orcid":true,"given":"Terry D.","family":"Crawford","sequence":"additional","affiliation":[{"name":"Genentech Inc. , , 1 DNA Way , , ,","place":["South San Francisco, California, United 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94080-4990"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Wu","sequence":"additional","affiliation":[{"name":"Genentech Inc. , , 1 DNA Way , , ,","place":["South San Francisco, California, United States, 94080-4990"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"Genentech Inc. , , 1 DNA Way , , ,","place":["South San Francisco, California, United States, 94080-4990"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5830-1517","authenticated-orcid":true,"given":"Manda K.","family":"Wong","sequence":"additional","affiliation":[{"name":"Genentech Inc. , , 1 DNA Way , , ,","place":["South San Francisco, California, United States, 94080-4990"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Racquel","family":"Corpuz","sequence":"additional","affiliation":[{"name":"Genentech Inc. , , 1 DNA Way , , 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https:\/\/www.who.int\/teams\/global-programme-on-tuberculosis-and-lung-health\/tb-reports\/global-tuberculosis-report-2025."},{"key":"2026100909095031300_cit3","doi-asserted-by":"publisher","first-page":"S26","DOI":"10.1016\/j.ijid.2022.03.011","article-title":"The WHO Global Tuberculosis 2021\nReport \u2013 Not so Good News and Turning the Tide Back to End\nTB","volume":"124","author":"Chakaya","year":"2022","journal-title":"Int. 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Microbiol."},{"issue":"3","key":"2026100909095031300_cit7","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.chom.2018.08.001","article-title":"Alveolar\nMacrophages Provide an Early Mycobacterium Tuberculosis Niche and\nInitiate Dissemination","volume":"24","author":"Cohen","year":"2018","journal-title":"Cell Host Microbe."},{"issue":"4","key":"2026100909095031300_cit8","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1084\/jem.20172020","article-title":"Growth\nof Mycobacterium Tuberculosis in Vivo Segregates with Host Macrophage\nMetabolism and Ontogeny","volume":"215","author":"Huang","year":"2018","journal-title":"J. Exp. Med."},{"issue":"7","key":"2026100909095031300_cit9","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/emmm.201000079","article-title":"Caseation\nof Human Tuberculosis Granulomas Correlates with Elevated Host Lipid\nMetabolism","volume":"2","author":"Kim","year":"2010","journal-title":"EMBO Mol. 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Agents\nChemother."},{"issue":"7","key":"2026100909095031300_cit13","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw376","article-title":"Official American Thoracic Society\/Centers\nfor Disease Control and Prevention\/Infectious Diseases Society of\nAmerica Clinical Practice Guidelines: Treatment of Drug-Susceptible\nTuberculosis","volume":"63","author":"Nahid","year":"2016","journal-title":"Clin. Infect. Dis."},{"issue":"8","key":"2026100909095031300_cit14","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1021\/acsinfecdis.6b00051","article-title":"Prediction of Drug Penetration in Tuberculosis Lesions","volume":"2","author":"Sarathy","year":"2016","journal-title":"ACS Infect. 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