Mark Brönstrup
Helmholtz Center for Infection Research, Braunschweig, Germany
Mark did his doctoral thesis in Organometallic Chemistry in the Gas Phase (with Prof. Dr. Drs. h.c. Helmut Schwarz) at the TU Berlin. He later became laboratory head for mass spectrometry at the Aventis Department of Chemistry in Frankfurt. Since 2014 Mark is Head of Department for Chemical Biology at the Helmholtz Centre for Infection Research, Braunschweig, and W3 professor at Leibniz University of Hannover. His research interests are the antibacterial and antiviral drug discovery with a focus on natural product-derived lead optimization as well as antibacterial drug conjugates. Moreover, he leads mode of action studies through metabonomics, intracellular drug quantification, peptide arrays, chemical pulldown experiments, pattern matching techniques (imaging, impedance measurements), including analytical method development.
Induction and quantification of drug uptake into Gram-negative bacteria
Infections caused by pathogenic bacteria represent a major health threat that is expected to rise further in the future. The need for novel antibiotics is currently not met by R&D efforts, in particular in the area of infections caused by Gram-negative bacteria. A main scientific hurdle is the lack of understanding how to assure a sufficient translocation of bioactive molecules across the Gram-negative cell wall.
A lead finding strategy with proven track record focuses on natural products from microorganisms that have solved the penetration problem in an evolutionary process. The cystobactamids, gyrase inhibitors isolated from Cystobacter sp., represent a novel lead series with an unusual structure composed of PABA oligomers and potent, broad spectrum activity against Gram negative bacteria. We will report three modular synthesis to cystobactamid analogs, and their application to generate (i) probes for cellular biology research and (ii) analogs with improved antibacterial properties and in vivoefficacy.
In an alternative lead finding strategy, our efforts to induce an active transport of small molecules into Gram negative bacteria will be presented. We report the design, synthesis and characterization of a series of theranostics agents based on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide (DOTAM) derivatives,[4] comprising siderophores that are internalized into Gram negative bacteria, inhibit bacterial growth and demonstrate efficacy to visualize bacterial infections in mice by optical imaging in vivo. In addition, three orthogonal approaches (growth recovery, FAP, fractionation coupled to LC/MS/MS) to quantify the intracellular accumulation of such conjugates will be presented.