Rational development of anti-infectives with novel target-sites and new mechanisms of action to overcome bacterial resistances

摘要

Bacterial resistances are on the rise which necessitates the development of novel anti-infectives to stay forearmed against bacterial infections. In this work, two different strategies were pursued to accomplish this goal. The “switch region” of bacterial RNA polymerase (RNAP) was chosen as a novel binding site, which was recently found to be targeted by the natural alpha-pyrone antibiotic myxopyronin. It is of particular interest as the alpha-pyrone antibiotics show no cross-resistance to the clinically used rifampicin. Based on a hit compound obtained during a pharmacophore-based virtual screening, a series of small molecule inhibitors was synthesized and their in vitro potency was evaluated. The resulting compounds display good antibacterial activity against Gram positive bacteria and Gram negative Escherichia Coli TolC, coming along with a reduced resistance frequency compared to rifampicin.Furthermore, mutasynthesis was investigated as an approach to generate myxopyronin derivatives. Thereby, the substrate specificity of the involved biosynthetic enzymes was determined and the production of several myxopyronin analogs was analytically proven.A second attempt aimed for a reduction of P. aeruginosa virulence by jamming its quorum sensing enzyme PqsD. The application of molecular docking complemented by biophysical methods enabled the rational design of potent PqsD inhibitors. Moreover the structural features of two distinct inhibitor classes could be successfully combined.