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SFB 630:  Recognition, Preparation and Functional Analysis of Agents against Infectious Diseases

Subject Area Chemistry
Biology
Medicine
Term from 2003 to 2015
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 5485822
 
Final Report Year 2015

Final Report Abstract

The goal of the Collaborative Research Center has been to support the identification and development of novel anti-infectives in an academic environment. Even though in the meantime the topic received much attention in politics worldwide, the overall situation does not appear much different today. In low-income countries, infections are still the leading cause of death. For a number of poverty-associated tropical infections (“neglected diseases”), the WHO roadmap for controlling, elimination or eradication of 2012 identified preventive chemotherapy as a key strategy, but there is still a lack of suitable and affordable drugs. Moreover, resistances against the major classes of antimicrobials are fast emerging and widespread in developed countries, too. In 2014, the WHO stated that a post-antibiotic era is a very real possibility for the 21st century. Hence, the search for novel anti-infectives is still as urgent today as in the beginning of the Collaborative Research Center and still justifies the involvement of academic science. We focused on the research for drugs against trypanosomes, Leishmania, Candida, mycobacteria, Legionella, staphylococci including MRSA, chlamydia and Neisseria. The extraordinary interdisciplinary cooperation of microbiologists, pharmacists, chemists, physicists, physicians, and computational chemists and biologists is evidenced by more than 460 peer-reviewed scientific publications. Here, some representative highlights will be given only: 1. Basic virulence and resistance mechanisms of pathogens have been analyzed in Candida albicans, for instance. In this fungus, resistance is mainly provoked by the expression of efflux pumps that is regulated by a subtle interplay of different transcription factors. Knowing their stimulation, activation, and impact on Candida fitness is a major premise to overcome antifungal resistance. 2. A major mechanism of African trypanosomes to invade the human immune system is antigenic variation. We could educe a model that mechanistically links this process to stage development of the parasite and hence points to a novel point of attack against African sleeping sickness. 3. Novel in-vivo imaging techniques were combined that allow for the first time the analysis of bacterial infection dynamics and kinetics on both sides, the pathogen development as well as the cellular immune response of the host in parallel and in real time. 4. We did not only investigate the mode of action of anti-infectives in cellular pathways like autophagy and apoptosis, but also down to the atomic level for their interaction with protein targets. The combined efforts of experts in structural biology, theoretical and computational chemistry, organic synthesis, and biochemistry lead to the development of a novel strategy for the tailor-made design of covalent protein ligands. From known structural interactions of irreversible protease inhibitors, corresponding covalent reversible inhibitors were designed by quantum mechanical calculations and docking studies. These inhibitors display favorable kinetic parameters in vitro, are highly active against trypanosomes and are - as anticipated - substantially less cytotoxic. 5. Regarding chemistry and pharmacy, novel routes for synthesis, structural characterization, and galenic formulation of anti-infectives were generated. For selected candidate molecules of quinolonamides, naphthylisoquinoline derivatives, pipecolic acid esters, and cinnamic acid derivatives, the efficacy in animal models for African trypanomiasis, malaria, melioidosis, or leishmaniasis has been evidenced – a key step for the takeover by product development organizations like “Drugs for neglected diseases initiative” or by the pharmaceutical industry.

Publications

 
 

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