## 1 Historical Overview of Antibiotic Use
aminoglycososides and fluoroquinolones [4; 17]. Also, there are an abundant number of efflux pumps in _Acinetobacter baumannii_ that enable resistance to tetracyclines, chloramphenicol, aminoglycos, fluoroquinolones, trimethoprim, and different \(\beta\)-lactams [12] Figure 2.  
Lateral or horizontal gene transfer is another method by which bacteria develop acquired resistance to antibiotics. The precise example that can be named here is the rapid spread of the _blaNDM-1_ gene in _Enterobacteriaceae_. This gene encodes a carbapenemase enzyme that further diminishes the effectiveness of carbapenem, a potentially powerful antibiotic [17]. Horizontal gene transfer occurs through three primary mechanisms: conjugation, transduction, and transformation [4]. Conjugation, in particular, is often facilitated under stressful conditions, such as exposure to antibiotics or heavy metals, which can drive the transfer of genetic material between bacteria [17]. In conjugation, DNA is shifted from a cell to another via adhesions on the cell surface or pili. The whole process is facilitated by conjugative machinery that is encoded by plasmid genes or the conjugative components in the chromosome. An example of this is extended-spectrum \(\beta\)-lactam resistance genes on plasmids spreading through the _Enterobacteriaceae_ and _pseudomonas_ families by conjugation [18]. In the transduction method, bacteriophages are involved. By transferring beneficial genes to another host, they can spread and boost their own survival as well. An observation of extracted bacteriophages from hospital-acquired MRSA infections has shown the successful transduction of antibiotic-resistant genes (ARGs) to vulnerable strains [19]. In both conjugation and transduction, plasmids are involved. Plasmids that are circular extrachromosomal DNA molecules can be transferred either via direct contact between bacterial cells in conjugation, or via bacteriophages in the transduction method [17]. In the latter method, transformation happens when the bacteria take up extracellular DNA fragments, leading them to be functionally expressed. Research  
Figure 2: This figure illustrates the various mechanisms through which bacteria can develop resistance to antibiotics. has indicated that _Helicobacter pylori_ is able to experience transformation and obtain genes through natural competence, and eventually turn into a virulent pathogen [20] (Figure 3). Sometimes, bacteria tolerate challenging conditions by altering their metabolic state. During the stationary phase, they can produce biofilm, which is another mechanism of resistance against antibiotics. Biofilms are organized communities of bacteria, placed in an extracellular matrix, that allow them to live on surfaces and impede antibiotic from penetrating and gaining access to bacteria; all in all, biofilms keeps bacteria safe and away from drugs and the immune system. Inside the biofilm, bacteria are able to communicate and match their resistance mechanisms. _P. aeruginosa_ is a classic example of a bacterium that forms biofilms in the airways of patients with cystic fibrosis. This bacterium can regulate the expression of superoxide dismutase and catalase, and eventually raise resistance against hydrogen peroxides. Also, the biofilm prevents the antibiotic from reaching the bacterial cell. Altogether, this leads to infection persistence and a chronic and recurrent state of cystic fibrosis [4]. Another interfering factor in antibiotic resistance in bacteria is the expression of the molecule (p) ppGpp. This mechanism represents a sophisticated adaptive strategy employed by bacteria in response to environmental stressors, such as exposure to antibiotics or nutrient deprivation. In such conditions, bacteria synthesize this molecule, and then the elevated level of (p) ppGpp leads to stress adaptation and the activation of survival mode. The bacteria prioritize the conservation of energy, so they downregulate replication and growth and start forming biofilms.