Deep mutational scanning of essential bacterial proteins can guide antibiotic development

Liselot Dewachter (), Aaron N. Brooks, Katherine Noon, Charlotte Cialek, Alia Clark-ElSayed, Thomas Schalck, Nandini Krishnamurthy, Wim Versées, Wim Vranken and Jan Michiels ()
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Liselot Dewachter: Centre of Microbial and Plant Genetics, KU Leuven
Aaron N. Brooks: Inscripta, Inc
Katherine Noon: Inscripta, Inc
Charlotte Cialek: Inscripta, Inc
Alia Clark-ElSayed: Inscripta, Inc
Thomas Schalck: Centre of Microbial and Plant Genetics, KU Leuven
Nandini Krishnamurthy: Inscripta, Inc
Wim Versées: Vrije Universiteit Brussel
Wim Vranken: Vrije Universiteit Brussel
Jan Michiels: Centre of Microbial and Plant Genetics, KU Leuven

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Deep mutational scanning is a powerful approach to investigate a wide variety of research questions including protein function and stability. Here, we perform deep mutational scanning on three essential E. coli proteins (FabZ, LpxC and MurA) involved in cell envelope synthesis using high-throughput CRISPR genome editing, and study the effect of the mutations in their original genomic context. We use more than 17,000 variants of the proteins to interrogate protein function and the importance of individual amino acids in supporting viability. Additionally, we exploit these libraries to study resistance development against antimicrobial compounds that target the selected proteins. Among the three proteins studied, MurA seems to be the superior antimicrobial target due to its low mutational flexibility, which decreases the chance of acquiring resistance-conferring mutations that simultaneously preserve MurA function. Additionally, we rank anti-LpxC lead compounds for further development, guided by the number of resistance-conferring mutations against each compound. Our results show that deep mutational scanning studies can be used to guide drug development, which we hope will contribute towards the development of novel antimicrobial therapies.

Date: 2023
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DOI: 10.1038/s41467-023-35940-3

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