## 1 Introduction  
Living organisms receive and process environmental stimuli through signal transduction pathways and respond through differential regulation of various cellular processes. Cyclic nucleotides that act as second messenger molecules play key roles in signaling pathways that sense environmental changes such as stress, temperature, nutrition, and pH in both prokaryotes and eukaryotes [1; 2; 3]. As second messengers, these cyclic nucleotides are involved in the transmission of the signals to effector molecules [1; 4]. The original second messenger molecule discovered was cyclic adenosine monophosphate (cAMP) through its role in metabolic pathways of eukaryotes, specifically, mammalian hormonal regulation [5; 6]. Since its initial discovery, cAMP has been found to act as a second messenger in a variety of organisms including many bacterial species and has diverse activity including roles in biofilm formation, expression of virulence factors, motility, and carbon metabolism [7]. Subsequently, several additional cyclic nucleotide second messengers have been discovered including cyclic guanosine monophosphate (cGMP), cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in a wide variety of organisms [2; 8; 9]. cGMP and c-di-GMP have been well characterized, particularly in Gram-negative bacteria. cGMP is involved in chemotaxis and UV stress-response, while c-di-GMP facilitates the transition from motile phase to adhesive phase and the expression of fimbiae in bacteria [3]. c-di-AMP is a new addition to the growing list of second messenger nucleotides and has since been identified in Gram-positive bacteria including _Listeria monocytogenes, Bacillus subtilis, Staphylococcus aureus_, and _Streptococcus_ spp., and in a few Gram-negative bacteria including _Chlamydia trachomatis_ and _Borrelia burgdorferi_[1; 10; 11; 12; 13; 14; 15; 16]. c-di-AMP has been implicated in diverse essential cellular processes including cell wall and membrane homeostasis, regulation of potassium ion channels, DNA damage repair, and sporulation (Table 1). Though c-di-AMP has been shown to play a critical role in many human pathogenic bacteria, neither its environmental stimuli nor the mechanisms controlling the regulation of cellular physiology and virulence are well understood [17; 15]. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Bacterium** & **Function of c-di-AMP** & \begin{tabular}{c} **c-di-AMP** \\ **Synthesis** \\ **Enzyme** \\ \end{tabular} & \
\begin{tabular}{c} **c-di-AMP** \\ **Degrading** \\ **Enzyme** \\ \end{tabular} &
\begin{tabular}{c} **Phenotype Involved in** \\ **an Altered Level of** \\ **c-di-AMP** \\ \end{tabular} & **Ref.** \\ \hline \multirow{6}{*}{_Bacillus subtilis_} & DisA binds to DNA and maintains DNA integrity. & & & & \\  & CdaS regulates & & & & \\  & sporulation. CdaA & & & & \\  & regulates cell wall & & & & \\  & synthesis and ion & & & & \\  & channel homeostasis. & & & & \\  & & & & & \\ \hline \multirow{6}{*}{_Listeria monocytogenes_} & Regulates cell wall & & & & \\  & homeostasis, resistance & & & & \\  & to acid, and carbon & & & & \\  & metabolism. & & & & \\  & & & & & \\ \hline \multirow{6}{*}{_Mycobacterium tuberculosis_} & Functions are not fully & & & & \\  & understood yet, but & & & & \\  & DisA is predicted to be & & & \\ \cline{1-1}  & involved in DNA repair. & & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: The function of cyclic di-adenosine monophosphate (c-di-AMP) and its synthesis and degradation enzymes in bacteria. c-di-AMP was first identified in a study of the DNA repair mechanism in _Thermotoga maritima_[29], and later, the same role of c-di-AMP in DNA repair was identified in _B. subtilis_[18; 29]. In a separate line of research, c-di-AMP was isolated from the cytosol of _L. monocytogenes_-infected host cells that were producing elevated levels of interferon \(\beta\)[16].