Nucleotide, c-di-GMP, c-di-AMP, cGMP, cAMP, (p)ppGpp signaling in bacteria and implications in pathogenesis

Abstract

For an organism to survive, it must be able to sense its environment and regulate physiological processes accordingly. Understanding how bacteria integrate signals from various environmental factors and quorum sensing autoinducers to regulate the metabolism of various nucleotide second messengers c-di-GMP, c-di-AMP, cGMP, cAMP and ppGpp, which control several key processes required for adaptation is key for efforts to develop agents to curb bacterial infections. In this review, we provide an update of nucleotide signaling in bacteria and show how these signals intersect or integrate to regulate the bacterial phenotype. The intracellular concentrations of nucleotide second messengers in bacteria are regulated by synthases and phosphodiesterases and a significant number of these metabolism enzymes had been biochemically characterized but it is only in the last few years that the effector proteins and RNA riboswitches, which regulate bacterial physiology upon binding to nucleotides, have been identified and characterized by biochemical and structural methods. C-di-GMP, in particular, has attracted immense interest because it is found in many bacteria and regulate both biofilm formation and virulence factors production. In this review, we discuss how the activities of various c-di-GMP effector proteins and riboswitches are modulated upon c-di-GMP binding. Using V. cholerae, E. coli and B. subtilis as models, we discuss how both environmental factors and quorum sensing autoinducers regulate the metabolism and/or processing of nucleotide second messengers. The chemical syntheses of the various nucleotide second messengers and the use of analogs thereof as antibiofilm or immune modulators are also discussed.

Structural and Biochemical Insight into the Mechanism of Rv2837c from Mycobacterium tuberculosis as a c-di-NMP Phosphodiesterase

“…Rv2837c May Regulate Both c-di-AMP and c-di-GMP Signaling Pathways in M. tuberculosis-Both c-di-AMP and c-di-GMP are important intracellular signaling molecules, and their homeostasis processes are regulated by many proteins in bacteria cells (3)(4)(5). c-di-GMP is down-regulated by EAL domain and HD-GYP domain, resulting in 5Ј-pGpG and GMP, respectively (6,39), whereas c-di-AMP is broken down by stand-alone DHH-DHHA1 domain and membrane-bound DHH-DHHA1, as well as HD domain to AMP and 5Ј-pApA, respectively (16,18,40).…”

“…The supernatant was separated and purified by HPLC with a C18 column (21.2 ϫ 250 mm; Sapphire). The following buffers were used in the gradient program: buffer A (10 mM NH 4 Ac, pH 5.0) and buffer B (100% methyl cyanide). The following protocol was used for separation (the values are times in minutes and percentage of buffer B used): 0.0, 3%; 20.0, 30%; 25.0, 30%; 26.0, 3%; 38.0, 3% at a flow rate of 10 ml min Ϫ1 ; with a diode array detector at 254 nm, the samples containing c-di-AMP were gathered.…”

“…many cellular processes (3)(4)(5). c-di-GMP regulates processes such as biofilm formation, motility, virulence, cell cycle, and type I interferon stimulation (6 -9).…”

Biofilm and Diabetic Foot Infections

“…Bakteriyel adaptasyonda kilit rol oynayan moleküllerden siklik diguanozin monofosfat (c-di-GMP), siklik diadenozin monofosfat (c-di-AMP), siklik guanozin monofosfat (cGMP), siklik adenozin monofosfat (cAMP) ve guanozin tetrafosfat (ppGpp) gibi ikincil mesajcı olarak görev alan nükleotidler biyofilm tedavisinde diğer bir hedeftir (74). Bir çalışmada diguaniat sentaz antagonistleriyle P. aeruginosa ve Acinetobacter baumannii'de biyofilm yapısının inhibe edildiği gösterilmiştir (75).…”

Antibiofilm Peptides: Potential as Broad-Spectrum Agents

“…In most bacteria, the two homologous proteins RelA and SpoT are responsible for modulating intracellular concentrations of ppGpp (51). Interestingly, the stringent stress response is highly conserved among Gram-negative and Gram-positive bacteria, but some bacteria (e.g., S. aureus) express only a single RelA/SpoT homolog, Rsh (30,37,51,52).…”