A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

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Synthesis of an oligopeptide library

The oligopeptides cystobactamid and Myxovalargin A are natural products produced by myxobacteria. Both secondary metabolites exhibit high antibacterial activity and are currently in different stages of preclinical antibiotic development. In the present work syntheses of these natural products and their analogs were performed to establish their total synthesis and to optimize their antibacterial profile, respectively. Cystobactamids represent a new class of antibiotics. Since their discovery structure-activity-relationships (SAR) were stated through natural product isolation and totalsynthesis. In this work the SAR studies were extended by synthesis of an agent library und the antibacterial profile was optimized against representatives of all ESKAPE pathogens utilizing structural simplification, bioisosterism and novel structural motifs. Myxovalargin A exhibits biological activity against tuberculosis. Insufficient access through fermentation prevented the elucidation of the absolute stereoconfiguration for a long time. Therefore, synthetic studies towards the total synthesis of Myxovalargin A were performed in this work with the long term aim to pave the way for a medicinal chemistry program. A combination solid and liquid phase synthesis enabled the provision of advanced fragments of the natural product

The myxobacterial antibiotic myxovalargin: Biosynthesis, structural revision, total synthesis and molecular characterization of ribosomal inhibition

Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. Pharmacokinetic and initial in vivo efficacy studies indicated that myxovalargin and analogues show potential for development as an antibacterial agent