Low-cost anti-mycobacterial drug discovery using engineered E. coli

Nadine Bongaerts, Zainab Edoo, Ayan A. Abukar, Xiaohu Song, Sebastián Sosa-Carrillo, Sarah Haggenmueller, Juline Savigny, Sophie Gontier, Ariel B. Lindner () and Edwin H. Wintermute ()
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Nadine Bongaerts: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Zainab Edoo: Sorbonne Université, Université Paris Cité, Inserm, Centre de Recherche des Cordeliers (CRC)
Ayan A. Abukar: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Xiaohu Song: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Sebastián Sosa-Carrillo: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Sarah Haggenmueller: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Juline Savigny: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Sophie Gontier: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Ariel B. Lindner: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics
Edwin H. Wintermute: Université Paris Cité, Inserm, System Engineering and Evolution Dynamics

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Whole-cell screening for Mycobacterium tuberculosis (Mtb) inhibitors is complicated by the pathogen’s slow growth and biocontainment requirements. Here we present a synthetic biology framework for assaying Mtb drug targets in engineered E. coli. We construct Target Essential Surrogate E. coli (TESEC) in which an essential metabolic enzyme is deleted and replaced with an Mtb-derived functional analog, linking bacterial growth to the activity of the target enzyme. High throughput screening of a TESEC model for Mtb alanine racemase (Alr) revealed benazepril as a targeted inhibitor, a result validated in whole-cell Mtb. In vitro biochemical assays indicated a noncompetitive mechanism unlike that of clinical Alr inhibitors. We establish the scalability of TESEC for drug discovery by characterizing TESEC strains for four additional targets.

Date: 2022
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DOI: 10.1038/s41467-022-31570-3

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