## 6 Multidrug Resistance of _A. baumannii_
### Mechanisms Responsible for A. buumannii Multidrug Resistance  
The main mechanisms conferring resistance to different classes of antibiotics include the presence of \(\beta\)-lactamases, modifying enzymes, permeability defects, alteration of target sites, and multidrug efflux pumps [177]. Severe hospital-acquired infections caused by _A. buumannii_ involve the use of carbapenems as highly effective drugs of choice used for the treatment of such infections [178]. Because of their broad spectrum, carbapenems are often active against microorganisms resistant to other antimicrobial compounds, and they are frequently used to treat complicated bacterial infections. Over the last few years, _A. buumannii_ MDR strains became increasingly resistant to carbapenems, the drug of choice to treat severe infections caused by these bacteria. The main cause of carbapenem resistance is the presence of oxacillinases (OXA), which belong to the Ambler class D \(\beta\)-lactamases. Over 400 OXA enzymes encoded by chromosome- or plasmid-located genes were characterized. Other classes of \(\beta\)-lactamases: class A, class B (metallo-\(\beta\)-lactamases, MBL), and class C (AmpC) were also identified in _A. buumannii_ strains [6; 179; 180; 181; 182; 183; 184; 185]. The most frequent MBLs in _A. buumannii_ are impenemases (IMPs), Verona inferon-encoded MBL (VIM), and MBL from New Delhi (NDM). Class C \(\beta\)-lactamases are encoded by the _ampC_ gene. Overexpression of _ampC_, regulated by an upstream insertion sequence (IS) element known as IS_Aha1_, is the main mechanism of resistance to third-generation cephalospor in _A. buumannii_[186]. Overexpression of the OXA and AmpC enzymes due to the presence of IS elements (see below), as well as the emergence of new OXA and AmpC variants, contributes to the increasing problem of _A. buumannii_ resistance [187; 188]. Another mechanism of _A. buumannii_ resistance is associated with enzymatic modification of the antimicrobial molecule. One of the best examples of resistance via modification of the drug is the presence of a large group of aminoglycos-modifying enzymes (AMEs). These enzymes possess unique substrate specificity and modify amino- or hydroxyl- groups of the aminoglycosides. There are three different types of AMEs, acetyltransferases, nucleotidyl transferases, and phosphotransferases, while all of them were identified in _A. buumannii_ isolates [6]. Proteomic analysis of _A. buumannii_ MDR strains shows protein variability that could be correlated with the appearance of resistance phenotypes, especially OMPs, which are involved in cellular drug uptake or efflux. The emergence of an antibiotic resistance level is often related to diverse variations in the expression of OMPs. It was found that, in _A. buumannii_, OmpA is strongly associated not only with adhesion to epithelial cells and biofilm formation, as mentioned earlier, but also with the modulation of cellular permeability and antibiotic resistance [103]. Importantly, changes in permeability frequently result in low-level resistance; therefore, the combination with other mechanisms, such as increased expression of efflux pumps, to confer a high-level antibiotic resistance phenotype is required [189]. Another common mechanism of antibiotic resistance in _A. buumannii_ is alteration of the target site or cellular functions [2]. This often results from spontaneous mutation of a bacterial gene on the chromosome. Modification of the target site results in decreased affinity for the drug molecule. One of the most known examples of target changes is enzymatic alteration of the binding site. In an alternative pathway, bacteria produce new proteins that protect the target against an antibiotic. Examples of drugs affected by this mechanism include fluoroquinolones and tetracyclines [190]. In _A. buumannii_, point mutations in the _gyrA/parC_ topoisomerases result in fluoroquinolones resistance, whereas a mutation in _rps_, the gene that encodes the ribosomal S10 protein, is responsible for tigecycline resistance [191].