1.3.2 Cyclic-di-GMP signalling Cycl

1.3.2 Cyclic-di-GMP signalling Cyclic diguanylate monophosphate (c-di-GMP) is a second messenger in bacteria that controls the switching between motile (planktonic) and sessile (biofilm) lifestyles, virulence of pathogens and other cellular functions (for reviews see71-73). The genes involved in its signaling pathways are conserved in bacteria but absent in animal species, rendering it as possible anti-infective target.74 High concentrations of c-di-GMP induce the synthesis of adhesins and exopolysaccharides (Pel, Psl, alginate) in P. aeruginosa and at the same time inhibit various forms of motility (Figure 3). In addition, c-di-GMP is involved in virulence control of pathogenic bacteria.75 C-di-GMP is synthesized by diguanylate cyclases (DGC), which harbor the specific amino acid sequence GGDEF in their active sites, and hydrolyzed by phosphodiesterases (PDE, containing an EAL or HD-GYP amino acid sequence domain) into linearized pGpG which can be further degraded to GMP. In P. aeruginosa many proteins carrying the GGDEF, EAL or even both domains are expressed,76 indicating that various input signals exist that control c-di-GMP signaling. To date, not all pathways are fully understood. Despite the high number of DGC and PDE enzymes, so far, only four effector proteins are characterized, i.e., proteins that bind c-di-GMP and activate or inhibit expression of the target genes or alter their function in response to c-di-GMP binding.