Fighting tuberculosis by drugs targeting nonreplicating Mycobacterium tuberculosis bacilli

Area of Science:

• Microbiology
• Drug Discovery
• Tuberculosis Research

Background:

• Current tuberculosis (TB) treatment regimens are lengthy and face challenges due to drug-resistant Mycobacterium tuberculosis (M.tb) bacilli.
• M.tb exists in various states within granulomas, including actively replicating (AR) and nonreplicating (NR) forms, complicating treatment.
• Existing in vitro models simulate NR M.tb through hypoxia, nutrient starvation, and acidic conditions.

Purpose of the Study:

• To evaluate the efficacy of various drugs against NR M.tb in different in vitro and in vivo models.
• To identify characteristics of drugs effective against NR M.tb in conditions mimicking the TB lung environment.
• To guide future TB drug development strategies.

Main Methods:

• Utilized in vitro models of NR M.tb (hypoxia, nutrient starvation, acid + nitric oxide, stationary phase).
• Tested drug activity against NR M.tb at different pH levels (5.8 and 7.3) under hypoxia.
• Employed conventional and C3HeB/FeJ mouse models to assess drug efficacy in vivo.

Main Results:

• Rifampin (RIF), rifapentine (RFP), PA-824 (PA), metronidazole (MZ), bedaquiline (BQ), and fluoroquinolones showed activity against NR M.tb in vitro.
• RIF and RFP were most effective against NR M.tb in hypoxia at neutral pH (7.3), mimicking caseum.
• Drug combinations sterilized conventional mouse models rapidly, but efficacy was reduced in mice with caseous granulomas.

Conclusions:

• Effective TB drug development requires targeting NR M.tb in hypoxic, neutral pH environments.
• Low lipophilic molecules, such as novel rpoB inhibitors with clogP < 3, are promising candidates.
• Achieving high unbound drug concentrations within caseum is crucial for eradicating persistent M.tb populations.