Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis

Bram Van den Bergh, Hannah Schramke, Joran Elie Michiels, Tom E. P. Kimkes, Jakub Leszek Radzikowski, Johannes Schimpf, Silke R. Vedelaar, Sabrina Burschel, Liselot Dewachter, Nikola Lončar, Alexander Schmidt, Tim Meijer, Maarten Fauvart, Thorsten Friedrich, Jan Michiels () and Matthias Heinemann ()
Additional contact information
Bram Van den Bergh: Centre of Microbial and Plant Genetics, Department of Molecular and Microbial Systems
Hannah Schramke: University of Groningen
Joran Elie Michiels: Centre of Microbial and Plant Genetics, Department of Molecular and Microbial Systems
Tom E. P. Kimkes: University of Groningen
Jakub Leszek Radzikowski: University of Groningen
Johannes Schimpf: Albert-Ludwigs-University of Freiburg
Silke R. Vedelaar: University of Groningen
Sabrina Burschel: Albert-Ludwigs-University of Freiburg
Liselot Dewachter: Centre of Microbial and Plant Genetics, Department of Molecular and Microbial Systems
Nikola Lončar: University of Groningen
Alexander Schmidt: University of Basel
Tim Meijer: University of Groningen
Maarten Fauvart: Centre of Microbial and Plant Genetics, Department of Molecular and Microbial Systems
Thorsten Friedrich: Albert-Ludwigs-University of Freiburg
Jan Michiels: Centre of Microbial and Plant Genetics, Department of Molecular and Microbial Systems
Matthias Heinemann: University of Groningen

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Antibiotic persistence describes the presence of phenotypic variants within an isogenic bacterial population that are transiently tolerant to antibiotic treatment. Perturbations of metabolic homeostasis can promote antibiotic persistence, but the precise mechanisms are not well understood. Here, we use laboratory evolution, population-wide sequencing and biochemical characterizations to identify mutations in respiratory complex I and discover how they promote persistence in Escherichia coli. We show that persistence-inducing perturbations of metabolic homeostasis are associated with cytoplasmic acidification. Such cytoplasmic acidification is further strengthened by compromised proton pumping in the complex I mutants. While RpoS regulon activation induces persistence in the wild type, the aggravated cytoplasmic acidification in the complex I mutants leads to increased persistence via global shutdown of protein synthesis. Thus, we propose that cytoplasmic acidification, amplified by a compromised complex I, can act as a signaling hub for perturbed metabolic homeostasis in antibiotic persisters.

Date: 2022
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DOI: 10.1038/s41467-022-28141-x

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