Chemical strategies toward bacterial communication and coordinated population behavior

• Applicant: Professor Dr. Thomas Böttcher
• Subject Area: Biological and Biomimetic Chemistry ; Biochemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250187465

Bacteria coordinate their population behavior via chemical signals and many pathogens use them to control their attack on the human host. This coordination of cells leads to the simultaneous production of so-called virulence factors such as toxins, enzymes, or certain secondary metabolites but also in some cases to changes in bacterial behavior such as formation of biofilms or swarming motility. These virulence factors and behaviors are frequently pivotal for invasion, escaping immune response and finally infecting the host organism. Certain bacterial secondary metabolites are key players in interspecies interactions and competition between bacteria, which also has major impact on the course of infectious diseases. Modulating or controlling these behaviors is thus of special interest and importance in order to develop new strategies for treating infectious diseases but also for use as molecular tools to increase our understanding of these dynamic mechanisms of adaptation. In the last years, we were able to develop chemical strategies to investigate antagonistic interactions of microorganisms along with strategies for modulating the coordination of behavior that leads to infectious diseases. The application for continuation of the program connects to our currently running studies and aims to investigate chemical modulators in four subprojects: 1) Further development of our metabolite-probe platform for the application in live cells of human pathogens. The platform aims to detect target proteins in a cell along with corresponding chemical probes with natural product ligands and thereby allows identifying the proteins as well as elucidating the chemical structures of the natural products. These probe-protein pairs may give rise to novel selective inhibitors for various cellular processes. 2) The development of targeted probes to label selectively the enzymes of quinolone-signal biosynthesis of the nosocomial pathogen Pseudomonas aeruginosa. 3) The search for natural product inhibitors of swarming behavior of pathogenic bacteria for which motility is associated with their infectious lifestyle and antibiotic tolerance. 4) The synthesis of a quinolone-N-oxide probe to discover the cellular targets of quinolone-N-oxides, which mediate interspecies interactions and have effects on virulence and growth of different pathogenic bacteria. The probe should also contribute to the development of novel selective inhibitors of the involved target enzymes. In conclusion, these four subprojects should demonstrate the potential of chemical modulators for customized control of bacterial virulence, which may generate novel lead-structures and strategies against infectious diseases.

• DFG Programme: Independent Junior Research Groups