FIGURE 2.

Cereulide toxin synthesis is the result of a complex and multi-layered process. Transcriptional regulation of the ces non-ribosomal peptide synthetase (NRPS) operon is tightly controlled by pleiotropic or metabolite-responsive transcriptional regulators such AbrB, Spo0A, and CodY. These ensure a correct timing of toxin synthesis within the cell cycle by integrating sporulation-inducing trigger factors and sensing the intrinsic nutritional and energy status of the cells by monitoring GTP and branched-chain amino acid (BCAA) levels. Although this ties cereulide formation to ceasing metabolic fitness levels, the unidirectional commitment to the developmental process of sporulation is induced later on by sigma factor H-dependent, self-reinforced levels of Spo0A-P, which are not affecting ces cluster transcription. Since cereulide formation significantly varies dependent on extrinsic stimuli, such as encountered in different food matrices, it is anticipated that additional transcriptional regulators could act on ces gene cluster expression. One prominent factor is oxygen availability, which might alike to CodY form a linker and an oppositely acting strategy for impinging the regulatory networks of virulence determination via PlcR/PapR and for that of cereulide formation. Solid arrows indicate a direct regulation while dashed arrows indicate an indirect regulatory effect.