The bacterial second messenger c-di-GMP: probing interactions with protein and RNA binding partners using cyclic dinucleotide analogs

Abstract

The ability of bacteria to adapt to a changing environment is essential for their survival. One mechanism used to facilitate behavioral adaptations is the second messenger signaling molecule bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP). c-di-GMP is widespread throughout the bacterial domain and plays a vital role in regulating the transition between the motile planktonic lifestyle and the sessile biofilm forming state. This second messenger also controls the virulence response of pathogenic organisms and is thought to be connected to quorum sensing, the process by which bacteria communicate with each other. The intracellular concentration of c-di-GMP is tightly regulated by the opposing enzymatic activities of diguanlyate cyclases and phosphodiesterases, which synthesize and degrade the second messenger, respectively. The change in the intracellular concentration of c-di-GMP is directly sensed by downstream targets of the second messenger, both protein and RNA, which induce the appropriate phenotypic response. This review will summarize our current state of knowledge of c-di-GMP signaling in bacteria with a focus on protein and RNA binding partners of the second messenger. Efforts towards the synthesis of c-di-GMP and its analogs are discussed as well as studies aimed at targeting these macromolecular effectors with chemically synthesized cyclic dinucleotide analogs.

A Look inside the Listeria monocytogenes Biofilms Extracellular Matrix

“…This molecule was found to be involved in biofilm formation and regulation in several bacterial species, i.e., regulation of alginate [ 78 ] and the glucose rich matrix polysaccharide Pel [ 79 ] biosynthesis in P. aeruginosa , and cellulose synthesis in many proteobacteria [ 80 , 81 , 82 ]. The c-di-GMP signaling networks are likely very complex, as a large number of c-di-GMP signaling proteins has been predicted in many bacterial species, and it is not clear how several input signals are integrated by microorganisms to control bacterial behavior [ 83 , 84 ]. Generally, high levels of c-di-GMP are required for bacteria to become sessile.…”

A c-di-GMP-Modulating Protein Regulates Swimming Motility of Burkholderia cenocepacia in Response to Arginine and Glutamate

“…C yclic- di meric- g uanosine m ono p hosphate or c-di-GMP is an intracellular second messenger present in a wide range of bacterial species (Camilli and Bassler, 2006 ). In response to a change in the bacterial milieu, temporal, and spatial c-di-GMP levels are controlled through sensing and regulatory mechanisms, which alter bacterial physiology and phenotypes (Shanahan and Strobel, 2012 ). Initially associated with exopolysaccharide synthesis and biofilm formation, the role of c-di-GMP is now established in the transitioning of bacterial lifestyle from planktonic to sessile, cellular development, host cell adherence, virulence, and motility (Ross et al, 1987 ; Paul et al, 2004 ; Simm et al, 2004 ; Lee et al, 2010 ; Römling et al, 2013 ).…”

Cyclic dinucleotide (c-di-GMP, c-di-AMP, and cGAMP) signalings have come of age to be inhibited by small molecules

“…So far, efforts to develop c-di-GMP signaling inhibitors have mainly been focused on finding inhibitors to interfere with c-di-GMP synthase DGC, 82,[86][87][88][89][90][91][92][93] PDE (EAL domain) 94,95 and riboswitches. 96,97 This is mostly because of the phenotypes that have been observed upon deletion of either DGC, PDE or their interacting partners.…”