Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy

Maxime Mistretta, Mena Cimino, Pascal Campagne, Stevenn Volant, Etienne Kornobis, Olivier Hebert, Christophe Rochais, Patrick Dallemagne, Cédric Lecoutey, Camille Tisnerat, Alban Lepailleur, Yann Ayotte, Steven R. LaPlante, Nicolas Gangneux, Monika Záhorszká, Jana Korduláková, Sophie Vichier-Guerre, Frédéric Bonhomme, Laura Pokorny, Marvin Albert, Jean-Yves Tinevez and Giulia Manina ()
Additional contact information
Maxime Mistretta: Microbial Individuality and Infection Laboratory
Mena Cimino: Microbial Individuality and Infection Laboratory
Pascal Campagne: Bioinformatics and Biostatistics Hub
Stevenn Volant: Bioinformatics and Biostatistics Hub
Etienne Kornobis: Bioinformatics and Biostatistics Hub
Olivier Hebert: CERMN
Christophe Rochais: CERMN
Patrick Dallemagne: CERMN
Cédric Lecoutey: CERMN
Camille Tisnerat: CERMN
Alban Lepailleur: CERMN
Yann Ayotte: Institut National de la Recherche Scientifique—Armand-Frappier Santé Biotechnologie Research Centre
Steven R. LaPlante: Institut National de la Recherche Scientifique—Armand-Frappier Santé Biotechnologie Research Centre
Nicolas Gangneux: Microbial Individuality and Infection Laboratory
Monika Záhorszká: Comenius University in Bratislava
Jana Korduláková: Comenius University in Bratislava
Sophie Vichier-Guerre: Epigenetic Chemical Biology Unit
Frédéric Bonhomme: Epigenetic Chemical Biology Unit
Laura Pokorny: Microbial Individuality and Infection Laboratory
Marvin Albert: Image Analysis Hub
Jean-Yves Tinevez: Image Analysis Hub
Giulia Manina: Microbial Individuality and Infection Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat.

Date: 2024
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DOI: 10.1038/s41467-024-48269-2

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