Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection.

@article{kofoed2026development,
  title = {{Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection.}},
  author = {Eric M Kofoed and Terry D Crawford and Christine M Bowman and Jessica Sims and Tahnee J Dening and Shumei Wang and Yuebiao Zhou and Seth F Harris and Min Xu and Ping Wu and Ying Yang and Manda K Wong and Racquel Corpuz and Yiming Xu and Anjani Ganti and Savita Ubhayakar and Chloe Hu and Kevin R Clark and Zhijuan Cai and Kwong Wah Lai and Xiaojing Wang and Renwei Zhang and Michael F T Koehler and Emily J Hanan and Ignacio Aliagas and Julie Ng and Jared Silverman and Khisimuzi Mdluli and Sharookh Kapadia and Man-Wah Tan},
  journal = {ACS infectious diseases},
  year = {2026},
  month = oct,
  doi = {10.1021/acsinfecdis.6c00350},
  url = {https://europepmc.org/article/MED/42917107},
  note = {CC BY-NC-ND},
}

TY  - JOUR
TI  - Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection.
AU  - Eric M Kofoed
AU  - Terry D Crawford
AU  - Christine M Bowman
AU  - Jessica Sims
AU  - Tahnee J Dening
AU  - Shumei Wang
AU  - Yuebiao Zhou
AU  - Seth F Harris
AU  - Min Xu
AU  - Ping Wu
AU  - Ying Yang
AU  - Manda K Wong
AU  - Racquel Corpuz
AU  - Yiming Xu
AU  - Anjani Ganti
AU  - Savita Ubhayakar
AU  - Chloe Hu
AU  - Kevin R Clark
AU  - Zhijuan Cai
AU  - Kwong Wah Lai
AU  - Xiaojing Wang
AU  - Renwei Zhang
AU  - Michael F T Koehler
AU  - Emily J Hanan
AU  - Ignacio Aliagas
AU  - Julie Ng
AU  - Jared Silverman
AU  - Khisimuzi Mdluli
AU  - Sharookh Kapadia
AU  - Man-Wah Tan
PY  - 2026
DA  - 2026/10/01
JO  - ACS infectious diseases
DO  - 10.1021/acsinfecdis.6c00350
UR  - https://europepmc.org/article/MED/42917107
AB  - 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 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.
SN  - 2373-8227
ER  -