4.8 Article

Intracellular localisation of Mycobacterium tuberculosis affects efficacy of the antibiotic pyrazinamide

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NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -

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NATURE RESEARCH
DOI: 10.1038/s41467-021-24127-3

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资金

  1. Francis Crick Institute
  2. Cancer Research UK [FC001092]
  3. UK Medical Research Council [FC001092]
  4. Wellcome Trust [FC001092]
  5. Australian Research Council Discovery Early Career Research Award
  6. Rebecca L Cooper Medical Research Foundation
  7. non-stipendiary FEBS long-term fellowship
  8. European Union [892859]
  9. Marie Curie Actions (MSCA) [892859] Funding Source: Marie Curie Actions (MSCA)

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It is crucial for tuberculosis chemotherapy to kill the intracellular population of the pathogen, and PZA accumulates and is most effective in acidified phagosomes. Combination with bedaquiline enhances PZA accumulation by a host-dependent process.
To be effective, chemotherapy against tuberculosis (TB) must kill the intracellular population of the pathogen, Mycobacterium tuberculosis. However, how host cell microenvironments affect antibiotic accumulation and efficacy remains unclear. Here, we use correlative light, electron, and ion microscopy to investigate how various microenvironments within human macrophages affect the activity of pyrazinamide (PZA), a key antibiotic against TB. We show that PZA accumulates heterogeneously among individual bacteria in multiple host cell environments. Crucially, PZA accumulation and efficacy is maximal within acidified phagosomes. Bedaquiline, another antibiotic commonly used in combined TB therapy, enhances PZA accumulation via a host cell-mediated mechanism. Thus, intracellular localisation and specific microenvironments affect PZA accumulation and efficacy. Our results may explain the potent in vivo efficacy of PZA, compared to its modest in vitro activity, and its critical contribution to TB combination chemotherapy. Effective chemotherapies against tuberculosis must kill the pathogen's intracellular population. Here, Santucci et al. show that bacterial localisation within human macrophages impact pyrazinamide (PZA) accumulation and efficacy, and that combination with a second antibiotic (bedaquiline) enhances PZA accumulation via a host-dependent process.

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