The rise of pathogenic bacteria that are resistant against a variety of antibiotic treatment emphasizes the need for novel active molecules. One promising novel class of active molecules is genetically encoded and ribosomally synthesized peptides, as they offer the potential to employ directed evolution approaches across a huge sequence space directly on an active substance in order to engineer novel activities and thus introduce a novel engineering principle into antibiotic development. However, in many cases the activity of the peptide molecule depends on substantial posttranslational modifications (PTMs) which give the peptides conformational stability and protect against proteolytic degradation. Consequently, the degrees of freedom in the engineering of such peptides on sequence level are highly dependent on the flexibility of the PTM-machinery to accept such changes. Here, we propose a synthetic biology approach to study systematically the flexibility of PTM-machineries for the class of lanthipepetides in order to assemble a highly flexible machinery that will support a broad range of engineering measures and thus optimize the chances to discover molecules with modified or completely novel activities. We also propose to implement a high-throughput screen for the bioactivity of these molecules in order to be able to engineer specific enzymes of the PTM-machinery for increased flexibility and to finally implement large scale directed evolution screens for novel antibiotic activities.
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