FOR 854: Post-genomic Strategies for New Antibiotic Drugs and Targets

抗生素比任何其他类别的医疗药物都有助于延长人类的预期寿命。然而，抗菌素耐药性在全球范围内以惊人的速度蔓延，并对健康构成巨大威胁。对新药的基础研究和开发重视不够，严重限制了治疗选择。研究单位的目标是利用后基因组时代的战略，研究有前途的新抗生素化合物、机制和靶点。该概念主要是生物学驱动的，并整合了微生物，生物化学，化学和制药研究，以确定新的抗生素范例。我们正在通过基因组挖掘寻找新的抗生素化合物，并正在建立合适的表达系统以产生变体。一个主要的重点将是新的抗生素机制，这可以帮助克服耐药性问题。这些机制包括有前途的新目标，如核糖开关和细胞内蛋白酶;对于后者，已经发现了一类高活性的新型抗生素天然化合物，酰基缩酚酸肽，并将进行详细分析。此外，具有已证实的抗生素活性的新天然化合物将被分析为有趣的新抗生素机制。特别关注具有复杂的双重或多重作用模式的天然化合物，如脂肽抗生素。由于细菌细胞壁生物合成是许多这些化合物的靶途径，因此将研究抗生素对膜结合的多酶生物合成机制的拓扑结构和动力学的影响，以确定新的抗生素活性和抗生素干预的新靶位点。在一个项目中，我们希望通过靶向寄生虫的细菌内共生体，将产生的知识直接转移到寄生虫的新治疗策略中。抗生素应用的历史表明，抗生素的使用不可避免地与耐药性的选择有关。因此，寻找新的抗生素化合物并研究新出现的耐药机制将是一项永久性任务，这一主题在相当长一段时间内尚未得到充分解决。在此背景下，我们的主要目标之一是为年轻科学家提供优秀的培训，以应对当前的挑战和未来的创新抗生素药物开发。

Antibiotics, more than any other class of medical drugs, have contributed to an increased life expectancy of humans. However, antibacterial resistance has spread globally at an alarming rate and presents a tremendous health threat. Inadequate attention to basic research and development of new drugs has seriously limited treatment options. The objective of the Research Unit is to investigate promising new antibiotic compounds, mechanisms and targets, using post-genome era strategies. The concept is primarily biology-driven and integrates microbiological, biochemical, chemical and pharmaceutical research to identify new antibiotic paradigms. We are searching for new antibiotic compounds through genome mining and are setting up suitable expression systems for generating variants. A major focus will be on novel antibiotic mechanisms, which can help to overcome the resistance problems. Such mechanisms include promising new targets such as riboswitches and intracellular proteases; for the latter, a highly active new class of antibiotic natural compounds, the acyldepsipeptides, has already been found and will be analysed in detail. In addition, new natural compounds with proven antibiotic activity will be analysed as to interesting new antibiotic mechanisms. A particular focus will be on natural compounds with complex dual or multiple modes of action such as lipopeptide antibiotics. Since bacterial cell wall biosynthesis is the target pathway for many of these compounds, the impact of antibiotics on the topology and dynamics of the membrane-bound multi-enzyme biosynthesis machinery will be studied to identify new antibiotic activities and new target sites for antibiotic intervention. In one project, we want to directly transfer the generated knowledge into new treatment strategies for parasites by targeting their bacterial endosymbionts. The history of application of antibiotics has demonstrated that usage is inevitably linked to selection of resistance. Therefore, it will be a permanent task to search for new antibiotic compounds and to study the emerging resistance mechanisms, a topic that has not been adequately addressed for quite some time. It this context, it is one of our main goals to provide excellent training for young scientists towards current challenges and for future development of innovative antibiotic drugs.