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

• DOI: 10.1038/s41467-021-25538-y
• Publication Date: 2021-09-01T10:04:51Z
• Authors: Hung-Ju Chang; Ana Zúñiga; Ismael Conejero; Peter L. Voyvodic; Jerome Gracy; Elena Fajardo-Ruiz; Martin Cohen-Gonsaud; Guillaume Cambray; Georges-Philippe ...; Magdalena Meszaros; Lucy Meunier; Jerome Bonnet
• Keywords: 0301 basic medicine; Bacteria; Science; Q; Biosensing Techniques; Gene Expression Regulation, Bacterial; Sensitivity and Specificity; Article; Liver Transplantation; Bile Acids and Salts; 03 medical and health sciences; Metabolic Engineering; Vibrio Infections; Escherichia coli; Humans; Pathology, Molecular; Carrier Proteins; Sequence Alignment; Biomarkers; Vibrio

AbstractBacterial 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.