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TB drug development: immunology at the table.

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  • 1Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.

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Summary

Host immune responses in tuberculosis (TB) impact drug distribution and create drug-tolerant Mycobacterium tuberculosis (Mtb). New TB drug discovery must target these tolerant Mtb subpopulations for effective treatment.

Keywords:
drug resistanceimmunopathologynon-replicationpersistencephenotypic toleranceviable but non-culturable

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Area of Science:

  • Microbiology
  • Immunology
  • Pharmacology

Background:

  • Host immune responses significantly influence tuberculosis (TB) pathogenesis and drug efficacy.
  • Mycobacterium tuberculosis (Mtb) exhibits phenotypic tolerance to drugs, particularly when replicating slowly or non-replicating.

Purpose of the Study:

  • To highlight how host-pathogen interactions inform TB drug discovery strategies.
  • To emphasize the need for pharmacokinetic evaluations in specific lesions and assays targeting tolerant Mtb.

Main Methods:

  • Review of host-pathogen interactions in TB drug discovery.
  • Discussion of challenges in in vitro screening for drugs against slow-replicating or non-culturable Mtb.
  • Analysis of pharmacokinetic evaluation beyond blood levels.

Main Results:

  • Host immunopathology affects drug distribution within TB lesions, necessitating lesion-specific pharmacokinetic measurements.
  • The host immune response induces phenotypic drug tolerance in Mtb subpopulations.
  • Current in vitro assays for drug-tolerant Mtb have limitations, and a reliable assay for 'viable but non-culturable' Mtb is lacking.

Conclusions:

  • TB drug discovery must account for host-mediated drug tolerance and distribution.
  • Targeting slow-replicating or non-replicating Mtb is crucial for developing novel TB therapies.
  • Development of assays to screen for drugs effective against tolerant Mtb is a priority for treatment shortening.