What does this research mean for the field?

Small-molecule inhibitors of inosine 5′-monophosphate dehydrogenase (GuaB) exhibit potent bactericidal activity against Mycobacterium tuberculosis and accelerate bacterial elimination when added to standard treatment regimens in advanced preclinical models. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To develop potent, orally bioavailable small-molecule inhibitors of inosine 5′-monophosphate dehydrogenase (GuaB) to overcome drug resistance in Mycobacterium tuberculosis infection.

September 14, 2026ACS Infectious DiseasesOpen Access

Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection

View Full Paper

Ask AI

Bookmark

Authors

EKEric M. KofoedOregon Health & Science University TCTerry D. CrawfordGenesys (United States)CBChristine M. BowmanMerck & Co., Inc., Rahway, NJ, USA (United States)

Discussion

Member takes

Implication

Preclinical study demonstrates rapid bacterial clearance by GuaB inhibitors in mouse tuberculosis models, suggesting therapeutic promise against complex infections.

Key Points

To develop potent, orally bioavailable small-molecule inhibitors of inosine 5′-monophosphate dehydrogenase (GuaB) to overcome drug resistance in Mycobacterium tuberculosis infection.
Synthesized orally bioavailable small-molecule inhibitors of GuaB and evaluated bactericidal activity across extracellular, intracellular, and hypoxic environments.
Tested inhibitor efficacy across multiple mouse models of lung infection: C57BL/6 super acute, C57BL/6 chronic, chronic BALB/c, and C3HeB/FeJ (Kramnik) models.
Evaluated a combination regimen adding GuaB inhibitors to bedaquiline, pretomanid, and moxifloxacin in the C3HeB/FeJ model featuring caseous necrotic granulomas.
GuaB inhibitors demonstrated bactericidal efficacy in C57BL/6 acute and chronic models, whereas no therapeutic benefit was observed in the chronic BALB/c intracellular model.
Addition of a GuaB inhibitor to bedaquiline, pretomanid, and moxifloxacin led to the rapid elimination of culturable infection in 50% of treated C3HeB/FeJ mice.

Cite This Study

Kofoed et al. (2026) studied this question.

synapsesocial.com/papers/6aa7b3aa0926e14a848b2d60 https://doi.org/10.1021/acsinfecdis.6c00350

View Full Paper

Ask AI

Bookmark

Implication

Preclinical study demonstrates rapid bacterial clearance by GuaB inhibitors in mouse tuberculosis models, suggesting therapeutic promise against complex infections.

Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection

Discussion

Member takes

Implication

Key Points

Cite This Study

Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection

Discussion

Member takes

Implication

Key Points

Cite This Study

Also Consider

Also Consider