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Franke R, Overwin H, Häussler S, et al. Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosa. mSystems. 2021;6(4):e0061021doi: 10.1128/mSystems.00610-21.
Franke, R., Overwin, H., Häussler, S., & Brönstrup, M. (2021). Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosa. mSystems, 6(4), e0061021. https://doi.org/10.1128/mSystems.00610-21
Franke, Raimo, et al. "Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosa." mSystems vol. 6,4 (2021): e0061021. doi: https://doi.org/10.1128/mSystems.00610-21
Franke R, Overwin H, Häussler S, Brönstrup M. Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosa. mSystems. 2021 Aug 31;6(4):e0061021. doi: 10.1128/mSystems.00610-21. Epub 2021 Jul 13. PMID: 34254824; PMCID: PMC8407119.
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mSystems. 2021 Aug 31;6(4):e0061021. doi: 10.1128/mSystems.00610-21. Epub 2021 Jul 13.

Targeting Bacterial Gyrase with Cystobactamid, Fluoroquinolone, and Aminocoumarin Antibiotics Induces Distinct Molecular Signatures in Pseudomonas aeruginosa.

mSystems

Raimo Franke, Heike Overwin, Susanne Häussler, Mark Brönstrup

Affiliations

  1. Department of Chemical Biology, Helmholtz Centre for Infection Researchgrid.7490.a, Braunschweig, Germany.
  2. Institute of Molecular Bacteriology, Twincore, Centre for Clinical and Experimental Infection Research, Hannover, Germany.
  3. Department of Molecular Bacteriology, Helmholtz Centre for Infection Researchgrid.7490.a, Braunschweig, Germany.
  4. German Centre for Infection Research (DZIF), Braunschweig, Germany.

PMID: 34254824 PMCID: PMC8407119 DOI: 10.1128/mSystems.00610-21

Abstract

The design of novel antibiotics relies on a profound understanding of their mechanism of action. While it has been shown that cellular effects of antibiotics cluster according to their molecular targets, we investigated whether compounds binding to different sites of the same target can be differentiated by their transcriptome or metabolome signatures. The effects of three fluoroquinolones, two aminocoumarins, and two cystobactamids, all inhibiting bacterial gyrase, on Pseudomonas aeruginosa at subinhibitory concentrations could be distinguished clearly by RNA sequencing as well as metabolomics. We observed a strong (2.8- to 212-fold) induction of autolysis-triggering pyocins in all gyrase inhibitors, which correlated with extracellular DNA (eDNA) release. Gyrase B-binding aminocoumarins induced the most pronounced changes, including a strong downregulation of phenazine and rhamnolipid virulence factors. Cystobactamids led to a downregulation of a glucose catabolism pathway. The study implies that clustering cellular mechanisms of action according to the primary target needs to take class-dependent variances into account.

Keywords: DNA gyrase; Pseudomonas aeruginosa; RNA sequencing; antibiotics; gyrase; metabolomics; mode of action

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