# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Virulence Factors
#### 4.1.4 Multiple Signalling Systems in the Regulation of Virulence Genes
The interaction of ppGpp and DkAs can also indirectly regulates the transcription process known as \(\sigma\)-factor competition. _P. aeruginosa_ has many \(\sigma\)-factors encoded in its genome, with 24 putative \(\sigma\)-factors identified so far [144]. In general, the \(\sigma\)-factor binds to the RNA polymerase core enzyme producing a holoenzyme. Once this happens, the \(\sigma\)-factor can recognize its cognate promoter sequence leading to a binding process between them. This facilitates the opening of the double-stranded DNA, leading to the initiation of transcription by allowing the transcription machinery to bind. In the end, elongation of the transcript from the template strand leads to the finished mRNA that can be then translated into proteins or processed further [144; 145]. \(\sigma\)-factors are responsible for the transcription of genes that are necessary under certain conditions. For example, \(\sigma\)-factor \(\sigma^{70}\) (also known as RpoD), is needed in exponential growth while \(\sigma^{38}\) (also known as RpoS), is needed in the stationary phase [143; 144]. Additionally, the expression of RpoS is important for tolerance against antibiotics during stationary phase [146]. The cyclic-3\({}^{\prime}\)5\({}^{\prime}\)-diguanylic acid (c-di-GMP) is another nucleotide-signaling molecule, playing a very important role in the post-transcriptional regulation of biofilm formation. This small molecule has the ability to increase the triggers for biofilm formation, meanwhile inhibiting motility [147]. The c-di-GMP signaling system is very complex and consists of two groups of proteins: diguanylate cyclase (DGCs) (containing GGDEF motif), responsible for c-di-GMP synthesis, and phosphodieserase (PDEs) (containing EAL or HD-GYP motif) involved in c-di-GMP degradation [3]. These enzymes control many factors, such as biosynthesis of adhesins and exopolysaccharide, motility, environmental stress adaptation, synthesis of secondary metabolites, virulence in animal and plant hosts, among others [148]. The transduction of phosphorylation events via the Gacs/GacA regulatory systems controls biofilm formation. In this Gacs/GacA two-component system, the RsmA RNA-binding protein negatively controls biofilm formation pathways, by inhibiting production of GGDEF/EAL encoding proteins and it consequently inhibits the increase in cyclic di-GMP levels. When _P. aeruginosa_ is under stress, this pathway generates RsmY and RsmZ (non-coding RNAs), which neutralize the translational repression activity of RsmA. Accordingly, there is an increase in the level of cyclic di-GMP, promoting the biosynthesis of polysaccharides (alginate and Pel) and resulting in biofilm formation [107]. Therefore, quorum sensing and the multiple different bacterial signaling systems have a major impact on bacterial control in relation to the environment and in the regulation of its various virulence factors. A better understanding of these multiple signaling systems will, in the future, allow for a better control and combat of bacterial infections.