Phenazine Biosynthesis Inhibitors as Pseudomonas aeruginosa Antivirulence Agents.
10 affiliations
- 1Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
- 2Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
- 3Department of Biological Sciences, Columbia University, New York, New York 10027, United States.
- 4Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany.
- 5Saarland University, Department of Pharmacy, Campus E8.,1 66123 Saarbrücken, Germany.
- 6PharmaScienceHub (PSH), 66123 Saarbrücken, Germany.
- 7German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 66123 Saarbrücken, Germany.
- 8Center of Pharmaceutical Engineering (PVZ), Technische Universität Braunschweig, 38106 Braunschweig, Germany.
- 9Institute of Biochemistry, Biotechnology and Bioinformatics, Technische Universität Braunschweig, 38106 Braunschweig, Germany.
- 10Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, 48149 Münster, Germany.
Abstract
Phenazines are redox-active secondary metabolites produced by a variety of bacteria, including Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen associated with severe, often chronic infections and particularly notorious for its multiple resistance mechanisms. A major contributor to P. aeruginosa virulence and resistance is the production of phenazine-derived metabolites such as pyocyanin, which play central roles in biofilm formation, redox homeostasis, and host tissue damage. Consequently, inhibition of phenazine biosynthesis may be an attractive pathoblocker strategy aimed at attenuating bacterial virulence without exerting bactericidal pressure, thus reducing the development of drug resistance. Over the past years, considerable progress has been made in the identification and characterization of small-molecule inhibitors targeting this pathway. These advances have been driven by interdisciplinary efforts, with medicinal chemistry, chemical biology, and structural biology providing key insights into target tractability, ligand binding modes, and structure-activity relationships. In this review, we summarize recent developments in phenazine biosynthesis inhibition, highlighting representative inhibitors and discussing biological and structural data for enzymes across the pathway.
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BibTeX
@article{handke2026phenazine,
title = {{Phenazine Biosynthesis Inhibitors as Pseudomonas aeruginosa Antivirulence Agents.}},
author = {Maria Handke and Janosch Baumgarten and Marie Thiemann and Moritz Zimmermann and Martin Empting and Lars E P Dietrich and Conrad Kunick and Wulf Blankenfeldt and Matthias Schiedel},
journal = {ACS bio \& med chem Au},
year = {2026},
month = sep,
doi = {10.1021/acsbiomedchemau.6c00146},
url = {https://europepmc.org/article/MED/42921315},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Phenazine Biosynthesis Inhibitors as Pseudomonas aeruginosa Antivirulence Agents.
AU - Maria Handke
AU - Janosch Baumgarten
AU - Marie Thiemann
AU - Moritz Zimmermann
AU - Martin Empting
AU - Lars E P Dietrich
AU - Conrad Kunick
AU - Wulf Blankenfeldt
AU - Matthias Schiedel
PY - 2026
DA - 2026/09/10
JO - ACS bio & med chem Au
DO - 10.1021/acsbiomedchemau.6c00146
UR - https://europepmc.org/article/MED/42921315
AB - Phenazines are redox-active secondary metabolites produced by a variety of bacteria, including Pseudomonas aeruginosa, a Gram-negative opportunistic pathogen associated with severe, often chronic infections and particularly notorious for its multiple resistance mechanisms. A major contributor to P. aeruginosa virulence and resistance is the production of phenazine-derived metabolites such as pyocyanin, which play central roles in biofilm formation, redox homeostasis, and host tissue damage. Consequently, inhibition of phenazine biosynthesis may be an attractive pathoblocker strategy aimed at attenuating bacterial virulence without exerting bactericidal pressure, thus reducing the development of drug resistance. Over the past years, considerable progress has been made in the identification and characterization of small-molecule inhibitors targeting this pathway. These advances have been driven by interdisciplinary efforts, with medicinal chemistry, chemical biology, and structural biology providing key insights into target tractability, ligand binding modes, and structure-activity relationships. In this review, we summarize recent developments in phenazine biosynthesis inhibition, highlighting representative inhibitors and discussing biological and structural data for enzymes across the pathway.
SN - 2694-2437
ER -