Lung microenvironments harbor Mycobacterium tuberculosis phenotypes with distinct treatment responses

Antimicrob Agents Chemother. 2023 Sep 19;67(9):e0028423. doi: 10.1128/aac.00284-23. Epub 2023 Aug 11.


Tuberculosis lung lesions are complex and harbor heterogeneous microenvironments that influence antibiotic effectiveness. Major strides have been made recently in understanding drug pharmacokinetics in pulmonary lesions, but the bacterial phenotypes that arise under these conditions and their contribution to drug tolerance are poorly understood. A pharmacodynamic marker called the RS ratio® quantifies ongoing rRNA synthesis based on the abundance of newly synthesized precursor rRNA relative to mature structural rRNA. Application of the RS ratio in the C3HeB/FeJ mouse model demonstrated that Mycobacterium tuberculosis populations residing in different tissue microenvironments are phenotypically distinct and respond differently to drug treatment with rifampin, isoniazid, or bedaquiline. This work provides a foundational basis required to address how anatomic and pathologic microenvironmental niches may contribute to long treatment duration and drug tolerance during the treatment of human tuberculosis.

Keywords: granuloma; pharmacodynamics; pharmacokinetics; tolerance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology
  • Antitubercular Agents / therapeutic use
  • Humans
  • Lung / microbiology
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred Strains
  • Mycobacterium tuberculosis* / genetics
  • Tuberculosis* / drug therapy


  • Antitubercular Agents