Nucleotide second messengers are critical transmitters of signaling in all living things. cAMP is used by bacteria and eukaryotes alike, whereas certain nucleotide second messengers are unique to bacteria. For example, guanosine tetraphosphate (ppGpp) is a key regulator of the stringent response in bacteria (Srivatsan and Wang, 2008) . Another nucleotide second messenger, cyclic-di-GMP (c-di-GMP), is a relatively recently appreciated cyclic ribonucleotide (Ross et al., 1987) synthesized by bacteria from two GTP precursors that are hydrolyzed and ultimately circularized via 5-to-3 monophosphate linkages. The bacterial diguanylate cyclases that synthesize c-di-GMP all contain a characteristic GGDEF domain, whereas the phosphodiesterases that specifically degrade c-di-GMP to pGpG contain an EAL domain. The GGDEF domain, and presumably c-di-GMP, appears to be limited to Bacteria (Galperin et al., 2001) and is not found in Archaea or Eukarya. c-di-GMP appears to play complex roles as a second messenger in most bacterial species, and regulates diverse processes, such as motility, biofilm formation, and virulence gene expression (Tamayo et al., 2007) . The molecular mechanisms by which c-di-GMP regulates these biological processes in bacteria are only beginning to be understood. It appears that c-di-GMP is capable of specific binding to regulatory proteins containing the PilZ protein domain (Cotter and Stibitz, 2007) . The PelD protein of P. aeruginosa is an additional non-PilZ-containing c-di-GMP sensor protein (Lee et al., 2007) .