## 1 Introduction  
Bacteria utilize a series of sensory systems to monitor the external environment and regulate cellular metabolic networks in a timely manner to adapt to stressful conditions. Most of these systems convert external stimuli into regulation of the intracellular concentration of secondary messengers, which modulate key molecular targets and polymorphic phenotypes [1]. Guanosine-5\({}^{\prime}\), 3\({}^{\prime}\)-pentaphosphate (ppGpp) and guanosine-5\({}^{\prime}\), 3\({}^{\prime}\)-tetraphosphate (ppGpp) (collectively referred to as (p)ppGpp) are common secondary messengers that were originally found to induce a decline in rRNA and tRNA synthesis in response to amino acid starvation [2; 3]. It is now known that several stress conditions, including both nutritional and environmental stimuli, induce an increase in intracellular (p)ppGpp concentration and lead to global changes in transcription profiles. This concentration-dependent reprogramming of cellular processes induced by (p)ppGpp is known as the stringent response. The RelA-SpoT Homologue (RSH) controls the cellular pool of (p)ppGpp. In most bacteria, a single RSH enzyme with both synthetic and hydrolytic activities can use GTP or GDP and ATP to generate (p)ppGpp and can also hydrolyze (p)ppGpp to yield pyrophosphate and GDP or GTP. Monofunctional RelA and SpoT proteins are generally found in Betaproteobacteria and Gammaproteobacteria. RelA harbors the synthetic activity, whereas SpoT is mainly responsible for (p)ppGpp degradation and has weak synthase activity [3; 4; 5]. In addition, short single-domain RSH proteins, including small alarmonesyntheases (SASs) and small alarmone hydrolases (SAHs), are present in various bacterial species [6; 7]. (p)ppGpp is induced by various stresses and regulates intracellular metabolic levels and polymorphic bacterial phenotypes. Transcriptome analysis showed that approximately 16-26% of the genes regulated by the stringent response are involved in DNA, tRNA, fatty acid, amino acid, and membrane component synthesis [8; 9]. Some studies have also reported impaired virulence, antibiotic resistance, and persistence in \(\Delta\)RSH mutants [10]. There are three mechanisms of response for regulating (p)ppGpp. Th first is by altering the binding preference of RNA polymerase (RNAP) to the promotes of downstream target genes. (p)ppGpp molecules bind to two distinct sites on RNAP, namely the \(\beta^{\prime}\)-\(\omega\) interface (site 1) and DksA-\(\beta^{\prime}\) interface (site 2) [11; 12; 13]. They regulate the formation and decay rates of RNAP-promoter complexes as well as the escape of RNAPs from promoters, which may be dependent on the DNA sequence of the promoters, enabling sophisticated control over numerous genes. In addition, (p)ppGpp work by directly interacting with target proteins, such as DNA initiation enzyme (DnaG) [14], translation initiation factor 2 (IF2) [15], and elongation factor G (EF-G) [16]. Many of these identified proteins are GTP-binding enzymes, suggesting that (p)ppGpp may regulate their activity by competing with them for intracellular GTP [17]. (p)ppGpp can also indirectly regulate the expression of downstream target genes through transcription factors, such as \(\alpha^{S}\), cyclic di-AMP, and CodY [18; 19; 20]. These direct and indirect mechanisms and interactions with RNAP described above complete the global regulation of the stringent response on bacterial transcriptional and polymorphic phenotypes. In addition to (p)ppGpp, the transcription factor DksA also plays a crucial role in the stringent response. According to bioinformatics analysis, DksA appears to be present in most Proteobacteria, but not in _Firmicutes_ or _Thermophiles_. It should be emphasized that such a statement is not definitive owing to our limited knowledge of the protein structure of DksA. In fact, globular proteins similar to DksA that do not contain a zinc finger were found in _Pseudomonas aeruginosa_ and _Rhodobacter sphaeroides_[21; 22].