Host-Pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, United Kingdom.
« Intracellular localisation of Mycobacterium tuberculosis affects efficacyof the antibiotic pyrazinamide »
Nature communications, 12(1), 3816. https://doi.org/10.1038/s41467-021-24127-3Santucci, P., Greenwood, D. J., Fearns, A., Chen, K., Jiang, H., & Gutierrez,M. G. (2021)
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Pierre SANTUCCI (28 years old, French) obtained his PhD (2018) in Molecular Microbiology under the supervision of Dr. Stéphane CANAAN (LISM CNRS-UMR7255) at the Institut de Microbiologie de la Méditerranée (IMM, Aix-Marseille University). Throughout his PhD, he was interested in the enzymatic mechanisms that allow pathogenic mycobacteria to use specific lipids in order to chronically persist within infected individuals. In 2019, he joined the group of Dr. Maximiliano GUTIERREZ at the Francis Crick Institute (London, United Kingdom) in order to develop high-resolution microscopy approaches to study the intracellular mode of action of anti-tuberculous drugs.
Contact
Pierre SANTUCCI, PhD
Marie Sklodowska-Curie – FEBS Postdoctoral Research Fellow
Host-Pathogen Interactions in Tuberculosis Laboratory
The Francis Crick Institute
1 Midland Rd,
London NW1 1AT
United Kingdom
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Twitter: @PSanTB
Summary of the article
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.
