Andreas Domröse

Heinrich Heine University Düsseldorf

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Jennifer Hage‐Hülsmann

Heinrich Heine University Düsseldorf

Anita Loeschcke

Heinrich Heine University Düsseldorf

Stephan Thies

Forschungszentrum Jülich

Karl‐Erich Jaeger

Hamburg University of Technology

Thomas Drepper

Forschungszentrum Jülich

Fabienne Hilgers

Heinrich Heine University Düsseldorf

Nick Wierckx

Forschungszentrum Jülich

Dennis Binder

Forschungszentrum Jülich

Dietrich Kohlheyer

Forschungszentrum Jülich

Robin Weihmann

Heinrich Heine University Düsseldorf

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Forschungszentrum Jülich

Heinrich Heine University Düsseldorf

Stadtwerke Jülich (Germany)

Norwegian Institute of Bioeconomy Research

Cluster of Excellence on Plant Sciences

RWTH Aachen University

Institut des Géosciences de l'Environnement

Hebrew University of Jerusalem

Technical University of Darmstadt

Weatherford College

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Pseudomonas putida rDNA is a favored site for the expression of biosynthetic genes

Scientific Reports (2019)

Andreas Domröse Jennifer Hage‐Hülsmann Stephan Thies Robin Weihmann Luzie Kruse

Abstract Since high-value bacterial secondary metabolites, including antibiotics, are often naturally produced in only low amounts, their efficient biosynthesis typically requires the transfer of entire metabolic pathways into suitable bacterial hosts like Pseudomonas putida . Stable maintenance and sufficient expression of heterologous pathway-encoding genes in host microbes, however, still remain key challenges. In this study, the 21 kb prodigiosin gene cluster from Serratia marcescens was used as a reporter to identify genomic sites in P. putida KT2440 especially suitable for maintenance and expression of pathway genes. After generation of a strain library by random Tn5 transposon-based chromosomal integration of the cluster, 50 strains exhibited strong prodigiosin production. Remarkably, chromosomal integration sites were exclusively identified in the seven rRNA-encoding rrn operons of P. putida . We could further demonstrate that prodigiosin production was mainly dependent on (i) the individual rrn operon where the gene cluster was inserted as well as (ii) the distance between the rrn promoter and the inserted prodigiosin biosynthetic genes. In addition, the recombinant strains showed high stability upon subculturing for many generations. Consequently, our findings demonstrate the general applicability of rDNA loci as chromosomal integration sites for gene cluster expression and recombinant pathway implementation in P. putida KT2440.

Prodigiosin

Pseudomonas putida

Gene cluster

10.1038/s41598-019-43405-1

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Natural biocide cocktails: Combinatorial antibiotic effects of prodigiosin and biosurfactants

PLoS ONE (2018)

Jennifer Hage‐Hülsmann Alexander Grünberger Stephan Thies Beatrix Santiago‐Schübel Andreas Klein

Bacterial secondary metabolites are naturally produced to prevail amongst competitors in a shared habitat and thus represent a valuable source for antibiotic discovery. The transformation of newly discovered antibiotic compounds into effective drugs often requires additional surfactant components for drug formulation. Nature may also provide blueprints in this respect: A cocktail of two compounds consisting of the antibacterial red pigment prodigiosin and the biosurfactant serrawettin W1 is naturally produced by the bacterium Serratia marcescens, which occurs in highly competitive habitats including soil. We show here a combinatorial antibacterial effect of these compounds, but also of prodigiosin mixed with other (bio)surfactants, against the soil-dwelling bacterium Corynebacterium glutamicum taken as a model target bacterium. Prodigiosin exerted a combinatorial inhibitory effect with all tested surfactants in a disk diffusion assay which was especially pronounced in combination with N-myristoyltyrosine. Minimal inhibitory and bactericidal concentrations (MIC and MBC) of the individual compounds were 2.56 μg/mL prodigiosin and 32 μg/mL N-myristoyltyrosine, and the MIC of prodigiosin was decreased by 3 orders of magnitude to 0.005 μg/mL in the presence of 16 μg/mL N-myristoyltyrosine, indicative of synergistic interaction. Investigation of bacterial survival revealed similar combinatorial effects; moreover, antagonistic effects were observed at higher compound concentrations. Finally, the investigation of microcolony formation under combined application of concentrations just below the MBC revealed heterogeneity of responses with cell death or delayed growth. In summary, this study describes the combinatorial antibacterial effects of microbial biomolecules, which may have ecological relevance by inhibiting cohabiting species, but shall furthermore inspire drug development in the combat of infectious disease.

Prodigiosin

Biocide

Serratia

10.1371/journal.pone.0200940

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Citations (42)