Imperial College London


Faculty of Natural SciencesDepartment of Chemistry

Culinary Education Designer



+44 (0)7752 464 869j.radzikowski Website




C763ChemistrySouth Kensington Campus





Publication Type

6 results found

Van den Bergh B, Schramke H, Michiels JE, Kimkes TEP, Radzikowski JL, Schimpf J, Vedelaar SR, Burschel S, Dewachter L, Lončar N, Schmidt A, Meijer T, Fauvart M, Friedrich T, Michiels J, Heinemann Met al., 2022, Mutations in respiratory complex I promote antibiotic persistence through alterations in intracellular acidity and protein synthesis., Nature Communications, Vol: 13, Pages: 1-17, ISSN: 2041-1723

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.

Journal article

Vedelaar SR, Radzikowski JL, Heinemann M, 2021, A robust method for generating, quantifying, and testing large numbers of escherichia coli persisters., Methods in Molecular Biology, Pages: 41-62

Bacteria can exhibit phenotypes that render them tolerant against antibiotics. However, often only a few cells of a bacterial population show the so-called persister phenotype, which makes it difficult to study this health-threatening phenotype. We recently found that certain abrupt nutrient shifts generate Escherichia coli populations that consist almost entirely of antibiotic-tolerant cells. These nearly homogeneous persister cell populations enable assessment with population-averaging experimental methods, such as high-throughput methods. In this chapter, we provide a detailed protocol for generating a large fraction of tolerant cells using the nutrient-switch approach. Furthermore, we describe how to determine the fraction of cells that enter the tolerant state upon a sudden nutrient shift and we provide a new way to assess antibiotic tolerance using flow cytometry. We envision that these methods will facilitate research into the important and exciting phenotype of bacterial persister cells.

Book chapter

Radzikowski J, Delmas L, Spivey A, Youssef J, Kneebone Ret al., 2021, The Chemical Kitchen: Towards Remote Delivery of an Interdisciplinary Practical Course, Journal of Chemical Education, ISSN: 0021-9584

Journal article

Radzikowski JL, Schramke H, Heinemann M, 2017, Bacterial persistence from a system-level perspective, CURRENT OPINION IN BIOTECHNOLOGY, Vol: 46, Pages: 98-105, ISSN: 0958-1669

Journal article

Radzikowski JL, Vedelaar S, Siegel D, Ortega AD, Schmidt A, Heinemann Met al., 2016, Bacterial persistence is an active sigma(S) stress response to metabolic flux limitation, Molecular Systems Biology, Vol: 12, Pages: 1-18, ISSN: 1744-4292

While persisters are a health threat due to their transient antibiotic tolerance, little is known about their phenotype and what actually causes persistence. Using a new method for persister generation and high‐throughput methods, we comprehensively mapped the molecular phenotype of Escherichia coli during the entry and in the state of persistence in nutrient‐rich conditions. The persister proteome is characterized by σS‐mediated stress response and a shift to catabolism, a proteome that starved cells tried to but could not reach due to absence of a carbon and energy source. Metabolism of persisters is geared toward energy production, with depleted metabolite pools. We developed and experimentally verified a model, in which persistence is established through a system‐level feedback: Strong perturbations of metabolic homeostasis cause metabolic fluxes to collapse, prohibiting adjustments toward restoring homeostasis. This vicious cycle is stabilized and modulated by high ppGpp levels, toxin/anti‐toxin systems, and the σS‐mediated stress response. Our system‐level model consistently integrates past findings with our new data, thereby providing an important basis for future research on persisters.

Journal article

Kotte O, Volkmer B, Radzikowski JL, Heinemann Met al., 2014, Phenotypic bistability in Escherichia coli's central carbon metabolism, Molecular Systems Biology, Vol: 10, Pages: 1-11, ISSN: 1744-4292

Fluctuations in intracellular molecule abundance can lead to distinct, coexisting phenotypes in isogenic populations. Although metabolism continuously adapts to unpredictable environmental changes, and although bistability was found in certain substrate‐uptake pathways, central carbon metabolism is thought to operate deterministically. Here, we combine experiment and theory to demonstrate that a clonal Escherichia coli population splits into two stochastically generated phenotypic subpopulations after glucose‐gluconeogenic substrate shifts. Most cells refrain from growth, entering a dormant persister state that manifests as a lag phase in the population growth curve. The subpopulation‐generating mechanism resides at the metabolic core, overarches the metabolic and transcriptional networks, and only allows the growth of cells initially achieving sufficiently high gluconeogenic flux. Thus, central metabolism does not ensure the gluconeogenic growth of individual cells, but uses a population‐level adaptation resulting in responsive diversification upon nutrient changes.

Journal article

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