# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Virulence Factors
#### 4.1.1 Secretion Systems
aeruginosa_, polyamines can induce resistance to aminoglycos and quinolone antibiotics. On the other hand, it was also shown that exogenous addition of spermidine and other polyamines increases the susceptibility to \(\beta\)-lactam antibiotics, trimethoprim, chloramphenicol, and nalidixic acid, by inducing the expression of the efflux pump _oprH-phoPQ_ operon and of an LPS modification operon [81; 83]. Thus, the identification of the spermidine signal and its transporter could provide a good approach to control infections by _P. aeruginosa_. The type V secretion system (T5 SS) is the simplest secretion pathway described so far. The T5 SS consists of autotransporters (AT or T5 aSS) and two-partner secretion systems (TPS or T5 bSS) [53]. Basically, in this system, proteins are transported to, and remain associated with, the outer face of the outer membrane, or are released into the extracellular medium after proteolytic cleavage [84]. The T5 aSS proteins are modular proteins consisting of a signal peptide at the extreme N terminus and a \(\beta\)-domain of 12 \(\beta\)-strands at the C terminus, connected by a \"passenger\" domain that harbors the catalytic domain of the protein. The signal peptide crosses the inner membrane and is subsequently cleaved. In the periplasm, the C terminus domain is inserted into the outer membrane and forms a \(\beta\)-barrel. This process results in the exposure of the passenger domain on the surface of the bacteria or its release into the extracellular medium after cleavage either by autoproteolysis or by a protease [53]. In _P. aeruginosa_, the EstA is the only characterized T5 aS [85]. EstA has an autotransporter esterase activity and is located on the outer side of the outer membrane. It has been shown to be important for the production of rhamn, which in turn affects cell motility and biofilm formation [86]. The T5 bSS is very similar to T5 aS, except that the passenger domain is called TpsA and the \(\beta\) domain TpsB, and both are independent proteins [87]. In general, the TpsA and TpsB proteins cross the inner membrane through the Sec export pathway. TpsA is converted to a pro-protein after maturation of its signal peptide. In the outer membrane, TpsB recruits TpsA through POTRA domains that interact with the TpsA T5 bSS motif. The pro-TpsA protein is subsequently cleaved to form a mature TpsA protein, which may remain anchored to the surface of the bacteria or be released into the extracellular milieu [53]. In the genome of PAO1, six groups of T5 bSS were noted, among which LepA/LepB, that secretes a protease influencing the host's response to bacterial infection. CdrA/CdrB is responsible for transporting CdrA to the outer membrane, promoting biofilm formation and auto-aggregation in liquid culture [88; 89]. The type VI secretion system (T6 SS) is also a needle-like complex and is widely spread in Gram-negative bacteria [90]. In this secretion system, proteins without a signal peptide, denominated by Hcp (hemolysin-coregulated protein) and VgrG (valine-glycine repeat), require a functional T6 SS for their release into the extracellular medium [91]. The crystal structure of the _P. aeruginosa_ Hcp1 protein reveals a hexameric ring structure, homologous to the tube domain of the T4 phage tail (gp19 protein). On the other hand, the conserved N-terminal region of VgrGs shares similarities with the T4 phage proteins (gp5 and gp27 proteins). The gp5 and gp27 multimers constitute the bacteriophage tail spike used for puncturing the bacterial envelope and to inject DNA into the cytoplasm [53]. Thus, it was proposed that recognition of the target cell and effective delivery occur in a similar way to bacteriophage entry in the host cell [92]. Other components of T6 SS are: a ClpV ATPase, a FHA regulatory domain protein that is the target of a pair of Ser/Thr kinase and phosphatase, DotU- and IcmF-like proteins, and an outer membrane lipoprotein [53]. In _P.