2026-10-12T15:25:52Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33676107 2026-09-12T18:04:18Z category_4 category_7 category_8 category_19 category_21 category_873 category_46 category_64 category_132 portal_63 item_type_3 month_year_09_2026

Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection Eric M. Kofoed (12517372) Terry D. Crawford (1817035) Christine M. Bowman (1367856) Jessica Sims (2140696) Tahnee J. Dening (3354791) Shumei Wang (167633) Yuebiao Zhou (5979737) Seth F. Harris (1503169) Min Xu (15203) Ping Wu (46628) Ying Yang (24175) Manda K. Wong (24837858) Racquel Corpuz (11860682) Yiming Xu (463410) Anjani Ganti (5815679) Savita Ubhayakar (1947682) Chloe Hu (3129915) Kevin R. Clark (1443892) Zhijuan Cai (24837861) Kwong Wah Lai (2421373) Xiaojing Wang (147040) Renwei Zhang (10922996) Michael F.T. Koehler (24837864) Emily J. Hanan (1346409) Ignacio Aliagas (1465009) Julie Ng (11357236) Jared Silverman (1484191) Khisimuzi Mdluli (3013587) Sharookh Kapadia (24837867) Man-Wah Tan (108526) Biochemistry Medicine Microbiology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Cancer Infectious Diseases novel antibiotic treatments moxifloxacin treatment regimen lethal progressive infection developed extremely potent deaths per year containing therapeutic regimen care treatment regimen de novo </ c infection model 6 super acute advanced disease pathology mtb lung infection culturable mtb infection capable preclinical models included guabi led mtb guab2 inhibitors primarily intracellular mtb vivo </ 6 chronic molecule inhibitors infectious disease heterogeneous disease circulating mtb three different results support rapid elimination orally bioavailable mouse models limiting step hypoxic environments guanine biosynthesis fej model chronic balb capture features 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′-monophosphate dehydrogenase (GuaB) that catalyze the rate-limiting step in <i>de novo</i> 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 <i>in vivo</i> 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. 2026-09-12T00:00:00Z Dataset Dataset 10.1021/acsinfecdis.6c00350.s001 https://figshare.com/articles/dataset/Development_of_GuaB_Inhibitors_to_Treat_Mycobacterium_tuberculosis_Infection/33676107 CC BY-NC 4.0