Programmable receptors enable bacterial biosensors to detect pathological biomarkers in clinical samples

Hung-Ju Chang, Ana Zúñiga, Ismael Conejero, Peter L. Voyvodic, Jerome Gracy, Elena Fajardo-Ruiz, Martin Cohen-Gonsaud, Guillaume Cambray, Georges-Philippe Pageaux, Magdalena Meszaros, Lucy Meunier and Jerome Bonnet ()
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Hung-Ju Chang: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Ana Zúñiga: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Ismael Conejero: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Peter L. Voyvodic: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Jerome Gracy: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Elena Fajardo-Ruiz: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Martin Cohen-Gonsaud: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Guillaume Cambray: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier
Georges-Philippe Pageaux: Saint Eloi Hospital, University of Montpellier
Magdalena Meszaros: Saint Eloi Hospital, University of Montpellier
Lucy Meunier: Saint Eloi Hospital, University of Montpellier
Jerome Bonnet: Centre de Biologie Structurale (CBS), INSERM U1054, CNRS UMR5048, University of Montpellier

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract Bacterial biosensors, or bactosensors, are promising agents for medical and environmental diagnostics. However, the lack of scalable frameworks to systematically program ligand detection limits their applications. Here we show how novel, clinically relevant sensing modalities can be introduced into bactosensors in a modular fashion. To do so, we have leveraged a synthetic receptor platform, termed EMeRALD (Engineered Modularized Receptors Activated via Ligand-induced Dimerization) which supports the modular assembly of sensing modules onto a high-performance, generic signaling scaffold controlling gene expression in E. coli. We apply EMeRALD to detect bile salts, a biomarker of liver dysfunction, by repurposing sensing modules from enteropathogenic Vibrio species. We improve the sensitivity and lower the limit-of-detection of the sensing module by directed evolution. We then engineer a colorimetric bactosensor detecting pathological bile salt levels in serum from patients having undergone liver transplant, providing an output detectable by the naked-eye. The EMeRALD technology enables functional exploration of natural sensing modules and rapid engineering of synthetic receptors for diagnostics, environmental monitoring, and control of therapeutic microbes.

Date: 2021
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DOI: 10.1038/s41467-021-25538-y

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