Multi-resistant infectious agents are a growing problem in everyday clinical life and are threatening the health of the population even in countries with a well-developed public infrastructure. Novel anti-infectives are therefore urgently needed. These drugs should be directed against biological targets in pathogens that do not occur in human cells. To prevent cross-resistance to established drugs, these targets should not be addressed by antibiotics that are already used therapeutically. The bacterial enzyme PhzF is a key enzyme in the biosynthesis of pyocyanin, a virulence factor from the group of phenazines found in relevant human pathogens. PhzF catalyzes the isomerization of 2,3-dihydro-3-hydroxyanthranilate into an isomeric aminoketone. Although the structure of PhzF is known, the protein has not yet been systematically used as a basis for the rational development of antibacterial agents.
In the project, ligands of the substrate binding site of PhzF are designed using methods of cheminformatics (docking, scoring). Subsequently, molecules identified as suitable are synthesized and tested for PhzF binding and the effects on pyocyanin biosynthesis with structural biology and biochemical methods. From the results, structure-activity relationships are generated and used to design optimized derivatives. The project is carried out in close cooperation with P. Schneider and W. Blankenfeldt (Helmholtz Zentrum für Infektionsforschung), who for the first time described the three-dimensional structure of PhzF and its enzymatic catalysis mechanism.
Name of Doctoral Researcher
Janosch Baumgarten
Name of Supervisor
Conrad Kunick
Institute / Department
Institute of Medicinal and Pharmaceutical Chemistry, TU Braunschweig
Contact details
janosch.baumgarten@tu-braunschweig.de