**2. Characteristics of** *H. pylori* **Antibiotic Resistance**

It has been previously demonstrated, that antibiotic resistance in *H. pylori* a result of mutations in its genome. Point mutations in the V domain of *23S* ribosomal RNA can change the affinity of clarithromycin for the peptidyltransferase loop and lead to resistance to clarithromycin [11–13]. The most common *23S* rRNA mutations associated with clarithromycin resistance are A2143G, A2142G, A2142C [11–13]. The sensitivity of *H. pylori* to clarithromycin is also affected by outer membrane proteins. Proteins such as HopT (BabB), HofC, and OMP31 were absent in clarithromycin-sensitive strains, and were only identified in clarithromycin-resistant strains of *H. pylori*. The mechanism of their association with antibiotic resistance is not yet to metronidazole resistance clear [11].

Mutations in the *rdxA* gene encoding oxygen-insensitive nitroreductase and in the *frxA* gene encoding flavin oxidase reductase are the main cause of resistance to metronidazole. Mutations in these genes reduce the ability of metronidazole to recover to active forms (NO2<sup>−</sup>, NO2 <sup>2</sup>−), which have a damaging effect on the bacterial DNA structure [14,15].

Levofloxacin is a fluoroquinolone, which acts via its interaction with DNA gyrase encoded by the *gyrA* and *gyrB* genes. DNA gyrase performs an important function: it promotes the separation of DNA strands during replication. Under the influence of levofloxacin, the process of DNA synthesis and the process of replication of a bacterial cell are disrupted. In levofloxacin-resistant strains of *H. pylori*, mutations were found in codons 87, 88, 91, 97 of the *gyrA* gene and in position 463 of the *gyrB* gene [11–13].

Amoxicillin belongs to the group of beta-lactams, interacts with penicillin-binding proteins and leads to the disruption of cell wall synthesis and destruction of *H. pylori*. Mutations that can interfere with cell wall synthesis disrupt the mechanism of action of amoxicillin: *pbp1A*, *pbp2*, *pbp3*, *hefC*, *hopC* and *hofH*. In addition, the effect of amoxicillin on *H. pylori* is further complicated by the fact that the bacterium itself produces beta-lactamases and there is a reduced membrane permeability for amoxicillin due to efflux pumps [16–18].

In a cohort of Taiwanese patients (*n* = 70) diagnosed with refractory *H. pylori* infection, 39 isolates were successfully cultured. *H. pylori* isolates were obtained from the gastric mucosa, subjected to phenotypic testing for sensitivity to amoxicillin and molecular analysis of genetic variants of the *pbp1A* amoxicillin resistance gene. 30 substitutions were identified (K352, K363, F366, G367, A369, V374, Q376, T386, F396, H409, S414, R418, F448, F473, D508, V509, T513, L530, T541, S543, T550, N561, G59 1, Y604, S615, K617, R618, F620, V622 and P623) in amoxicillin-resistant isolates. It is noted that the majority of resistant isolates carry the P623L substitution, which is potentially responsible for the development of resistance to amoxicillin. Three amino acid substitutions (D479E, D535N and S589G) were identified in all amoxicillin-resistant *H. pylori* isolates obtained from Taiwanese patients [19].

Tetracycline, an antibiotic from the tetracycline group, destroys the codon-anticodon bond at the level of the 30S ribosome subunit, which halts bacterial protein synthesis. Mutations in the *16S rRNA* of the *TET-1* gene lead to the development of resistance to tetracycline. The most common genetic alteration is the substitution of the AGA-GGA triplet (926–928) [20].

The bactericidal action of rifabutin is realized due to its interaction with DNAdependent RNA polymerase and leads to inhibition of the process of transcription of bacterial DNA. Resistance to rifabutin arises due to mutation of the *rpoB* gene, which encodes the beta subunits of RNA polymerase [1].

Furazolidone (nitrofuran), affects the activity of bacterial oxidoreductase, thus disrupting bacterial metabolism. Mutations associated with resistance to this antibiotic have been identified in the *porD* and *oorD* genes encoding integral ferredoxin-like subunits [21].

Despite the fact that the factors ensuring the adaptation of *H. pylori* to antibiotics are already known, in particular: the effect of the efflux pump, membrane permeability, changes in outer membrane proteins, the ability to form a biofilm and mutations in number of genes, the molecular mechanisms of some remain unclear. Thus, the matter of prescribing effective therapy against *H. pylori* for patients with antibiotic resistance to several drugs remains open [1,22].
