Regulation of the Synthesis and Secretion of the Iron Chelator Cyclodipeptide Pulcherriminic Acid in Bacillus licheniformis.

The cyclodipeptide pulcherriminic acid synthesized by Bacillus licheniformis is an iron chelator that antagonizes certain pathogens by removing iron from the environment. But since the insoluble iron-pulcherriminic acid complex cannot act as an iron carrier as siderophores do, excessive synthesized pulcherriminic acid causes iron starvation for the producer cells. At present, the regulation of pulcherriminic acid synthesis and the mechanism by which B. licheniformis strikes a balance between biocontrol and self-protection from excessive iron removal remain unclear. This study provides insights into the regulatory network and explains the mechanism of pulcherriminic acid biosynthesis. The yvmC-cypX synthetic gene cluster was directly negatively regulated by three regulators: AbrB, YvnA, and YvmB. Within the regulatory network, YvnA expression was repressed not only by AbrB but also by iron-limiting environments, while YvmB expression was repressed by YvnA. The transporter gene yvmA is repressed by YvmB and is required for pulcherriminic acid secretion. The biosynthesis window is determined by the combined concentration of the three regulators in an iron-rich environment. Under iron-limiting conditions, cells close the pulcherriminic acid synthesis pathway by downregulating YvnA expression.IMPORTANCE The cyclodipeptides are widespread in nature and exhibit a broad variety of biological and pharmacological activities. The cyclodipeptide scaffold is synthesized by nonribosomal peptide synthetases (NRPSs) and cyclodipeptide synthases (CDPSs). At present, it is clear that CDPSs use aminoacyl tRNAs as substrates to synthesize the two peptide bonds, and the pulcherriminic acid synthase YvmC is a member of the eight identified CDPSs. However, little is known about the regulation of cyclodipeptide synthesis and secretion. In this study, we show that AbrB, which is considered to be the main regulator of NRPS-dependent pathways, is also involved in the regulation of CDPS genes. However, AbrB is not the decisive factor for pulcherriminic acid synthesis, as the expression of YvnA determines the fate of pulcherriminic acid synthesis. With this information on how CDPS gene transcription is regulated, a clearer understanding of cyclodipeptide synthesis can be developed for B. licheniformis Similar approaches may be used to augment our knowledge on CDPSs in other bacteria.