Project #13081
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#13081 : Hamper cell-to-cell variation to enhance drug-mediated killing
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Organisms :
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Name of Applicant : Giulia MANINA
Date of application : 20-03-2019
Unit : Microbial Individuality and Infection
Location : Calmette - 04 - 15
Phone : +33 (0)1 45 68 87 45
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Project context and summary :

Without new treatment development tuberculosis could cause about 70 million deaths by 2050, mostly due to the spread of multidrug-resistant strains. The standard drug regimen still builds on the first drugs introduced decades ago, and takes 6 months in the case of drug-sensitive tuberculosis, and up to 2 years in the case of drug-resistant tuberculosis, with heavy side effects. This long therapeutic regimen often results in patients not being able to follow it or complete it correctly, which promotes the chronicity of the infection and ultimately the onset of drug resistance. Although a few new molecules have been discovered, improving both the quality and the duration of tuberculosis chemotherapy remain pressing needs. Furthermore, the failure of chemotherapy is not only due to genetic resistance, which takes relatively long to occur, but also to the intrinsic ability of mycobacteria to diversify in discrete phenotypic states, which can endure drugs even in the absence of genetic mutations. This phenomenon, known as persistence, can eventually favor the onset of resistance, with major repercussions on disease control. In sum, tuberculosis therapy presents many challenges and in our view it is critical to study the ability of a drug or a drug combination to sterilize discrete subpopulations, which may either pre-exist in the population or result from adaptive processes. We found that, prior to drug exposure, phenotypically distinct subpopulations exist that display different drug susceptibility. In light of this, we hypothesized that phenotypic variation from cell to cell favors persistence and can consequently bring about treatment failure. Here we aim to identify molecules that reduce phenotypic variation, making the population more uniformly and rapidly susceptible to standard treatment. To this end, we developed a microfluidic system that allows us to track single cells by live imaging and to carry out a screening at the single-cell level, looking for molecules that homogenize the bacterial population and enhance the effectiveness of the standard treatment. Our approach could ultimately offer original therapeutic strategies towards better control of tuberculosis.

Related team publications :
"Preexisting variation in DNA integrity predicts the fate of single mycobacterial cells under stress" - Manina et al., 2019 - Under peer-review in The EMBO Journal.
PMID: 27837741; DOI: 10.1128/microbiolspec.TBTB2-0021-2016
PMID: 25779320; DOI: 10.1007/978-1-4939-2450-9_14
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Project Type : Short
Status : Pending

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