Antibiotics of the ADEP and empedopeptin class - Molecular modes of action and studies on bacterial resistance

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ADEPs (an acronym for a novel class of acyldepsipeptides) and empedopeptin are natural products or derivatives thereof with promising antibacterial activity. At project start, their mechanisms of action had been poorly explored. During the previous funding period we determined the target of empedopeptin and elucidated how ADEPs dysregulate target function. It turned out that empedopeptin binds to several lipid-bound peptidoglycan precursors and prevents the activity of distinct late-stage peptidoglycan synthesis enzymes in vitro. We apply for further funding to verify the specific region of the peptidoglycan precursors recognised by empedopeptin. ADEPs act on an unprecedented target, the bacterial Clp-protease. Since project start, we performed various biochemical experiments to study the molecular nature of target inhibition and the ADEP-ClpP co-crystal structure was solved. ADEP blocks important binding sites at ClpP for regulatory partner molecules and triggers opening of the gated entry pores to the proteolytic chamber resulting in untimely degradation of flexible or nascent bacterial proteins. We also found that a preferred target is the cell division protein FtsZ. We apply for further funding to explore the molecular reason for this particular sensitivity of FtsZ and to search for further preferred degradation targets of ADEP-activated ClpP by proteomics. In addition, we plan to investigate the molecular nature of spontaneous bacterial resistance against ADEPs by analysing exemplary pathogen genera from the target level to the infection process.