Cyclic di-GMP-Dependent Regulation of Antibiotic Biosynthesis in Lysobacter

Lysobacter enzymogenes is an environmental bacterium that secrets a heat-stable antifungal factor, HSAF, an antibiotic against crop fungal pathogens. Elevated levels of cyclic di-GMP inhibit HSAF synthesis. The transcription factor cAMP receptor-like protein Clp binds to two sites upstream of the promoter of the HSAF biosynthesis operon and activates gene expression. At elevated cyclic di-GMP levels, cyclic di-GMP binding to Clp compromises binding to DNA, particularly at the low-affinity binding site, which results in lower expression of the HSAF biosynthesis operon. Two cyclic di-GMP phosphodiesterases contribute the most to cyclic di-GMP-dependent regulation of HSAF production. One of them, the GGDEF-EAL protein, LchP, forms a protein complex with Clp. Such specificity of targeted action allows LchP that has relatively weak phosphodiesterase activity, to play an oversized role in Clp-dependent HSAF biosynthesis. The HD-GYP phosphodiesterase RpfG is another major phosphodiesterase, whose activity is increased at higher cell density via a quorum-sensing mechanism. Further, a common regulator of type IV pilus synthesis, PilR, modulates HSAF biosynthesis via an as yet uncharacterized cyclic di-GMP signaling pathway. These findings represent novel insights into cyclic di-GMP-dependent antibiotic biosynthesis regulation in an agriculturally important bacterium.