# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Antibiotic Resistance
#### 4.3.2 Acquired Resistance  
Although there is intrinsic resistance to certain antibiotics without prior exposure to antibiotics, acquired resistance is a consequence of antibiotic exposure, which leads to the selection of chromosomal genetic mutations or horizontal acquisition of genetic elements (plasmids, transposons, among others) [185]. For example, plasmids do not harbor essential genes for bacterial functioning under normal conditions, but contain genes that are advantageous for bacterial growth and multiplication under unfavorable conditions, such as the antibiotic resistance genes, heavy metal resistance, and virulence genes [186]. However, plasmid typing in _P. aeruginosa_ is particularly complicated due to insertion, deletion, co-integration, and exchange events that determine a low phylogenetic agreement between plasmid core genes [187]. Although acquisition of resistance genesis not as common in _P. aeruginosa_ as in many other bacteria, it has been shown to acquire plasmid-encoded carbapenemases (single metallo- \(\beta\)-lactamases) that can hydrolyse most \(\beta\)-lactams, including carbapenems [188]. [PERSON] and collaborators demonstrated that reducing antibiotic use alone is not enough to combat antibiotic resistance, as plasmids are transferred at high rates even in the absence of antibiotic selection [189]. Horizontal gene transfer occurs by transformation, transduction, and conjugation. It is an important means for bacteria to acquire several resistance genes from their counterparts, as is the case of acquisition of resistance to aminoglycos, fluoroquinolones, and \(\beta\)-lactam resistance genes [190]. Resistance to colistin (polymyxin E), an antibiotic that belongs to the polymyxin family, can be plasmid-mediated through mobilization of the _mcr-1_ gene [191].  
Interference with antibiotic targets is also a common strategy that bacteria use to prevent the action of antibiotics. For instance, modification of quinolone target sites is one such resistance mechanism. Quinolones inhibit bacterial DNA replication by targeting DNA gyrase and topoisomerase IV. When mutations in the _gyrA-gyrB_ and _parC-parE_ genes (encoding DNA gyrase and topoisomerase IV, respectively) occur, there is a decrease in the binding affinity of the encoded proteins to quinolones, resulting in greater resistance to these antibiotics in _P. aeruginosa_[192].  
In _P. aeruginosa_, one of the acquired resistance mechanisms is resistance to carbapenems, which involves mutations that lead to loss (by a mutation in the _qprD_ gene itself or in one of its regulatory proteins, such as mexT) or reduction in the production of the OprD specific outer membrane porin channel [193]. Mutations in the _mexT_ gene not only reduce OprD expression but also increase MexEF-OprN expression, leading to higher resistance to imipenem and antibiotics that are substrates for this pump [194].  
Another well-studied mechanism of acquired resistance in _P. aeruginosa_ is the mutations that cause overexpression of enzymes that inactivate antibiotics [192]. In clinical isolates of _P. aeruginosa_, AmpC overexpression was mostly associated _ampC_ gene mutations, a gene encoding the _ampC_ repressor. This led to the overproduction of \(\beta\)-lactamases and consequently, greatly increased resistance to cephalosporions [151; 195].