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.