# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Antibiotic Resistance
#### 4.3.1 Intrinsic Antibiotic Resistance
\(\beta\)-lactamases can be divided into four classes, on the basis of their amino acid sequences: A, B, C, and D. Class B \(\beta\)-lactamases are metalloenzymes that require divalent zinc ions for \(\beta\)-lactam hydrolysis. On the other hand, classes A, C, and D hydrolyse \(\beta\)-lactams through an active site serine [177]. The expression of \(\beta\)-lactamase AmpC confers a low level of resistance to aminopenicillins and most cephalospororins strongly induce the production of AmpC, which consequently hydrolyses these substrates [174]. In wild-type basal expression of _ampC_, during normal cell wall recycling, 1,6-anhydromuropeptides are removed from the cell wall and transported into the cytoplasm via the AmpG permease. The 1,6-anhydromuropeptides are cleaved by AmpD to generate free tripeptides, which are later converted into UDP-MurNAc-pentapeptides. This UDPMurNAc-pentapeptide interacts with AmpR bound to the _ampR-ampC_ intergenic region, creating a conformation that represses transcription of _ampC_, resulting in lower production of AmpC [174]. In the presence of a \(\beta\)-lactam antibiotic, it enters the periplasmic space through the outer membrane porins and interacts with specific PBPs. Because of the increase in 1.6-anhydromuropeptides pools, AmpD is unable to efficiently process the higher levels of those fragments. Anhydro-MurNAc peptides replace UDP-MurNAc-pentapeptides and then bound to AmpR, resulting in a conformational change in the protein. AmpR is converted to a transcriptional activator, _ampC_ is expressed at higher levels leading to the increase of AmpC in the periplasmic space [174; 178]. AmpC, being a \(\beta\)-lactamase, interacts with the antibiotic leading to its degradation. _P. aeruginosa_, through the acquisition of ESBL genes, can also produce extended-spectrum-\(\beta\)-lactamases (ESBLs)which confer a high degree of resistance to the majority of \(\beta\)-lactam antibiotics, including penicillins and cephalosporyrins [179]. Antimicrobial peptides (AMPs) are also promising models for the development of new antib Biofilm drugs. To date, more than 3000 natural AMPs have been isolated and characterized have been isolated and characterized [180]. Natural and artificially synthesized AMPs can be a gold mine for the development of new antimicrobial agents [181]. Due to their mechanism of action, which depends on the permeabilization of bacterial membranes, AMPs exhibit numerous advantages such as: (1) broad-spectrum activity; (2) low tendency to induce resistance and (3) high potential to target metabolically dormant cells that are found at a high rate within microbial biofilms [182]. There are numerous AMPs that have already been studied for their antimicrobial activity. Example, HBD2 (human beta-defensin 2), in nanomolar concentrations, and regardless of its chiral status, significantly reduces biofilm formation in _P. aeruginosa_ without affecting its metabolic activity. This reduction in biofilm formation adds importance to the role of HBD2 in innate host defense during the initial interaction between host and pathogen [183]. Another study performed with semi-synthetic peptide lin-SB056-1 and its dendrimic derivative (lin-SB056-1)2-K demonstrated that lin-SB056-1 was effective in reducing _P. aeruginosa_ biofilm formation and that the dimeric derivative (lin-SB056-1) 2-K demonstrated greater biofilm inhibitory activity compared to lin-SB056-1 [182]. Analogs of jelleine-1, another AMP, were synthesized for their study of antimicrobial functions and toxicity. However, jelleine-1 has been shown to have low antimicrobial potency against the gram-negative and gram-positive bacteria tested. In order to overcome this obstacle, an attempt was made to replace amino acids in order to make it more effective. It was shown that the introduction of Trp and Arg in the jelleine-1 sequence significantly increased its antimicrobial efficiency [181]. Although more studies are needed for this AMP, it is a potential candidate for the treatment of gram-negative bacterial infection.