**4. Antibacterial resistance and its mechanisms**

Bacterial resistance to antibacterial drugs increasingly becomes a major health and economic problem, eroding the discovery of antibiotics and their application to clinical medicine. As early as 1946, Alexander Fleming predicted that "There is probably no chemotherapeutic drug to which in suitable circumstances the bacteria cannot react by in some way acquiring 'fastness' (resistance)." Today it is really the truth. Resistance to the antibiotics will emerge only a few years after it is introduced to clinic use [20]. Bacterial resistance is positively cor‐ related with the use of antibacterial agents in clinical practice [21; 22]. Because any use of antibiotics can increase selective pressure in a population of bacteria, allowing survival of the resistant bacteria and death of the susceptible ones. We can find that pathogenic bacteria are resistant to practically all available antibacterial drugs. And many strains, which are in‐ formally called superbugs, are even resistant to several different antibiotics. Multidrug re‐ sistance has been found in Pseudomonas aeruginosa (P. aeruginosa), Acinetobacterbaumannii (A. baumannii), E. coli, and Klebsiellapneumoniae (K. pneumo‐ niae), producing extended-spectrum β-lactamases (ESBL), vancomycin-resistant enterococci Enterococcus faecium (E. faecium) (VRE), MRSA, vancomycin-resistant S. aureus VRSA, ex‐ tensively drug-resistant (XDR) Mycobacterium tuberculosis (M. tuberculosis), Salmonella enterica (S. enterica) serovar Typhimurium, Shigelladysenteriae (S. dysenteriae), Haemophi‐ lusinfluenzae (H. influenzae), Stenotrophomonas, and Burkholderia [23; 24].

**4.1. Genetics of antibiotic resistance**

*4.1.1. Mutations*

*4.1.1.1. Spontaneous mutations*

*4.1.1.2. Hypermutators*

*4.1.1.3. Adaptive mutagenesis*

*4.1.1.4. Horizontal gene transfer*

33].

ance phenotype in Pseudomonas aeruginosa [30].

Resistance can be an intrinsic property of the bacteria themselves or it can be acquired. There are two main ways of acquiring antibiotic resistance: i) chromosomal mutations and ii) horizontal gene transfer. But the question is where the horizontal gene comes from? Some of these genes have an environmental origin and began their evolution before the antibiotic era; most likely, the primary genes originated and diversified within the environmental bac‐

The Antibacterial Drug Discovery http://dx.doi.org/10.5772/52510 293

These mutations occur randomly as replication errors or an incorrect repair of a damaged DNA in actively dividing cells, presenting an important mode of generating antibiotic resist‐ ance. They are also called the growth dependent mutations. Quinolone resistance in Escheri‐ chia coli resulted from the mutations in at least seven positions in the gyrA gene or three positions in the parC gene [29]. There are a large number of biochemical mechanisms of an‐ tibiotic resistance related to Spontaneous Mutations. For instance, Mutations in mexR can cause derepression of the mexAB-oprM multidrug efflux operon, causing a multidrug resist‐

During a prolonged non-lethal antibiotic selective pressure a small bacterial population en‐ ters a transient state of a high mutation rate which is called hypermutable state. Hypermuta‐ tors are found in many bacteria species such as E. coli, S. enterica, Neisseria meningitides (N. meningitides),H. influenzae, S. aureus, Helicobacter pylori (H. pylori), Streptococcus pneumoniae (S. pneumoniae),and P. aeruginosa [85]. Various studies suggested that hyper‐ mutations play an important role in acquisition of antibiotic resistance in pathogens [31; 32;

Adaptive mutations arise in non-dividing or slowly dividing cells during the presence of a non-lethal selective pressure that favours them. A great number of antibiotic resistant mu‐

Horizontal transfer of genetic material between bacteria is the most commonly used way to spread antibiotic resistance. In general, this exchange is accomplished mainly through the processes of transduction (via bacteriophages), conjugation (via plasmids and conjugative transposons), and transformation (via incorporation into the chromosome of chromosomal DNA, plasmids, and other DNAs) [34]. This type of genetic transfer not only occurred be‐ tween closely related bacteria but can also occur between phylogenetically distant bacterial

tants may come from this mutation process under bacterial natural conditions [85].

terial communities, then mobilized and penetrated into pathogens. [27; 28]

Great amount of antibiotic is used in nonhuman niches, leading to the spread of resistant bacteria too. Antibiotics have been used for improving the production of livestock and poul‐ try for more than 50 years [25]. The Institute of Food Technologists (IFT), once convened a panel of internationally renowned experts to address the concern that, the emergence of an‐ timicrobial resistance may result from abuse in food production, manufacturing, and else‐ where [26].

Over the past several years, people struggled to search for the mechanisms of resistance. Therefore today there is a large pool of information about how drug resistances come out. Biochemical and genetic aspects of antibiotic resistance mechanisms are shown in Fig. 1.

**Figure 1.** Kinds of antibiotic resistance mechanisms [85].
