# Genomic and Metabolic Characteristics of the Pathogenicity in Pseudomonas aeruginosa
## 4 Metabolic Pathways Associated with Pathogenicity
### Antibiotic Resistance
#### 4.3.1 Intrinsic Antibiotic Resistance  
The intrinsic antibiotic resistance means the innate ability to decrease the effectiveness of a particular antibiotic through structural or functional characteristics conferring protection against toxic molecules and antimicrobials [166]. _P. aeruginosa_ exhibits lower outer membrane permeability compared to other Gram-negative bacteria. The Gram-negative membrane is an asymmetric bilayer of phospholipid and LPS, and it works as a selective barrier to prevent the penetration of antibiotics [167]. To survive, _P. aeruginosa_ must allow the entry of nutrients. This entry is accomplished through a collection of \(\beta\)-barrel proteins producing water-filled diffusion channels called porins [168]. The family of porins can be divided into four classes: non-specific porins, specific porins, gated porins, and efflux porins. Non-specific porins, the main of which is OprF, allow the slow diffusion of most small hydrophilic molecules. Specific porins, OprB, OprD, OprE, OprO, and OprP, have specific sites that bind to a particular set of molecules. Gated porins, TonB-dependent, OprC, and OprH, are responsible for the uptake of ion complexes. The OprM, OprN, and OprJ efflux porins are important components of efflux pumps [169]. Porins not only play an important role in the transport of sugars, amino acids and other nutrients, but are also involved in the transport of certain hydrophilic antibiotics such as \(\beta\)-lactams, aminoglycosoides, tetracyclines, and some fluoroquinolones [168]. In _P. aeruginosa_, one of the intrinsic mechanisms is the limitation of entry of hydrophilic antibiotics, through decreased outer membrane permeability, by reducing the number of non-specific porins proteins and replacing the porins with specific or selective channels that absorb only the necessary nutrients [170]. The other intrinsic mechanisms occur in carbapenem-resistant clinical strains of _P. aeruginosa_, which have been shown to be deficient in the OprD porin. Efflux pumps also play an important role in intrinsic antibiotic resistance. These efflux pumps can be substrate-specific or can extrude a wide range of compounds, including antibiotics from several structurally unrelated classes [171]. Efflux pumps have been classified in five superfamilies, namely: ATP-binding cassette, small multidrug resistance, major facilitator, resistance-nodulation-division (RND), and multidrug and toxic compound extrusion. PAO1 genome encodes multiple efflux pumps from all five superfamilies, but the resistance-nodulation-division (RND) type is the most prevalent [172; 173]. The four most important RND efflux pumps are MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY/OprM(OprA). There are other forms of multidrug efflux pumps, but they are not expressed in wild-type strains, albeit they may contribute to adaptive resistance such as MexJK, MexGHI-OpmD, MexVW, MexPQ-OpmE, MexMN, and TriABC [174]. It was demonstrated that the MexEF-OprN and MexGHI-OpmD sets can modulate QS systems by exporting the quinolone signalling molecule PQS, reducing its concentration and, consequently, reducing the production of the virulence factors, which favours the establishment of chronic infections [175]. The pumps consist of three components: an efflux transporter in the inner membrane, an outer membrane channel, and an accessory protein connecting the two in the periplasm. In this complex, the inner membrane protein captures the substrates from either the phospholipid bilayer in the inner membrane of the bacterial cell envelope or the cytoplasm and transports them into the extracellular medium via the outer membrane protein. The cooperation between these proteins is mediated by a periplasmic protein [173]. Another intrinsic resistance determinant in _P. aeruginosa_ is the inducible _ampC_ gene, encoding the hydrolytic enzyme \(\beta\)-lactamases [176].