**1. Background**

Antimicrobial resistance has become a serious public health problem in recent years. This problem has been increasing and is currently a truly global crisis that offers one of the worst forecasts of catastrophic scenarios in public health worldwide.

A sign of the seriousness of the problem is the fact that World Health Organization (WHO)'s new Global Antimicrobial Surveillance System (GLASS) reported the widespread occurrence of antibiotic resistance among 500,000 people with suspected bacterial infections across 22 countries [1].

Likewise, Centers for Disease Control (CDC)'s Antibiotic Resistance Threats in the United States (US), in 2019 (2019 AR Threats Report), reported that more than 2.8 million antibiotic-resistant infections occur in the US each year, and more than 35,000 people die as a result. Besides, 223,900 cases of *Clostridium difficile* occurred in 2017 and at least 12,800 people died [2].

Many bacteria produce important infections in human health, either due to community-acquired infections, nosocomial infections, or at intensive care units. Among these, many have an important phenotypic profile of antibiotic resistance. For example, *Staphylococcus aureus, Enterococcus* spp.*, Enterobacteriaceae* (other than *Salmonella* and *Shigella*), *Pseudomonas aeruginosa,* and *Acinetobacter* spp. [3, 4].

To classify these microorganisms according to the degree of resistance and acquired resistance profiles, a group of experts in the field of antimicrobial resistance in joint work with the European Center for the Prevention of Diseases and Control (ECDC) and the CDC established the definitions and characteristics among resistant bacteria: multidrug-resistant (MDR), extensively drug-resistant (XDR), and pan drug-resistant (PDR) bacteria [3, 4].

To establish objective parameters of the phenotypic resistance profile in each of these bacteria, epidemiologically significant antimicrobial categories were established. These categories were established based on the documents and cutoff points of the Clinical Laboratory Standards Institute (CLSI), the European Antimicrobial Sensitivity Testing Committee (EUCAST), and the US Food and Drug Administration (FDA) [3, 4].

Based on the new limits and definitions: MDR bacteria possess acquired resistance to at least one antibiotic of three or more categories; XDR bacteria possess resistance to at least one antibiotic of almost all categories, except one or two of them; and PDR bacteria are resistant to all agents of all categories of antimicrobials [3, 4].

Antimicrobial resistance has been observed in all families of antibiotics, including the latest generation and intrahospital antibiotics such as quinolones.

The wide use of quinolones in clinical practice includes the administration of the antibiotic in prophylaxis, in neutropenic patients with cancers, in cirrhotic patients at risk for spontaneous bacterial peritonitis, and in urologic surgery, among others. In many of these cases, strains with varying degrees of resistance to quinolones have been isolated [5, 6].

#### **2. History**

In 1962, quinolones were discovered as an important treatment for various pathological manifestations. The first one was nalidixic acid, which was synthetically produced by George Lesher at the Sterling-Winthrop Research Institute. It was synthesized from the isolation of chloro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid years before, as a product derived from the synthesis of chloroquine [7]. Its origin dates back to the use of chloroquine as an antimalarial agent. It was until years after its development that nalidixic acid was approved for the treatment of urinary tract infections by Gram-negative bacteria. This compound does not have an important effect on Gram-positive bacteria, in addition to having a certain cytotoxic effect on the gastrointestinal tract and the central nervous system. Its effect on Gram-negative bacteria is characteristic of the first generation of quinolones [8].

#### **3. Epidemiology**

The indiscriminate prescription of quinolones worldwide has led to a rapid increase in bacterial resistance. *Acinetobacter* spp., *Campylobacter* spp., *Capnocytophaga* spp., *Clostridium* spp.*, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis,* 

**27**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

*Klebsiella pneumoniae*

*\**

**Table 1.**

*Pseudomonas aeruginosa*

**Bacteria Mean resistance** 

**percentage**

29.7% 31.6% Iceland

19.3% 19.7% Estonia

*Acinetobacter* spp. 43.7% 36.2% Belgium

*Escherichia coli* 22.8% 25.3% Iceland

*EARS-Net 2015 and Ecdc. SURVEILLANCE REPORT. 2018 [11, 12].*

*Profile of resistance to quinolones of European countries (2015 vs. 2018).*

**4. The structure of quinolones**

(**Figure 1**) [13, 15–17].

organisms (**Figure 1**) [7, 18, 19].

but also on Gram-positive ones (**Figure 1**) [13, 14].

*Neisseria gonorrhea, Proteus mirabilis, P. aeruginosa, Salmonella* spp., *S. aureus,* and *Streptococcus pneumoniae,* among others, have been reported as resistant [7, 9, 10]*.* The ECDC collects and reports through the European Antimicrobial Resistance Surveillance Network (EARS-Net) information of seven bacterial pathogens that commonly cause infections in humans: *Acinetobacter* spp., *Enterococcus faecalis, Enterococcus faecium*, *Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae,* and *Pseudomonas aeruginosa.* Information comparing their profile of resistance to quinolones in Europe between 2015 and 2018 can be found in **Table 1** [11, 12]*.*

**Country with the lowest resistance percentage**

(0%)

(6.8%)

(2.9%)

(0%)

*The EARS-Net report does not contain information about quinolone resistance to other bacteria. Adapted from:* 

**2015 2018 2015 2018 2015 2018**

Norway (0%)

Finland (11.4%)

Iceland (0%)

Malta (0%)

**Country with the highest resistance percentage**

> Croatia (96.1%)

Cyprus (42.4%)

Poland (68.2%)

Slovakia (52.4%)

Greece (94.9%)

Cyprus (45.5%)

Slovakia (70%)

Romania (59%)

The structure of quinolones derives from two types of rings, a naphthyridine core with a nitrogen molecule in positions 1 and 8. Through this structure, the compound is limited to being used as a therapy against Gram-negative bacteria. However, it has been shown that by inserting a cyclopropyl group in the first position of the nitrogen ring, an effect is achieved not only on Gram-negative bacteria

The second generation was developed in 1980, from the addition of a fluorine atom at position six, resulting in fluoroquinolones. These have higher activity in Gram-negative bacteria, as well as Gram-positive bacteria. Some fluoroquinolones can inhibit all Gram-negative organisms. Quinolones with piperazine on carbon 7 are effective in Gram-negative bacteria and the signaling of topoisomerase 4

Later, the third generation arises by adding certain molecules in the rings, such as the cyclopropyl ring in the first position of nitrogen, improving the activity in Gram-positive bacteria. Some of these modifications achieved sensitivity in organism resistant to different antibiotics, including *Streptococcus pneumoniae*. Other benefits of this generation are a longer life in serum and activity against anaerobic

The fourth generation was later developed by incorporating nitrogen in the eighth position, resulting in a broad-spectrum antibiotic. Its action in some Grampositive organisms is more effective compared to the other generations; however, its activity in anaerobic organisms is limited. It has a superior bacterial selectivity to avoid a high level of resistance and its toxic effects are less unfavorable than in the other generations [7, 8]. Thanks to the modifications made to the quinolones,


*\* The EARS-Net report does not contain information about quinolone resistance to other bacteria. Adapted from: EARS-Net 2015 and Ecdc. SURVEILLANCE REPORT. 2018 [11, 12].*

#### **Table 1.**

*Antimicrobial Resistance - A One Health Perspective*

in 2017 and at least 12,800 people died [2].

and pan drug-resistant (PDR) bacteria [3, 4].

Drug Administration (FDA) [3, 4].

been isolated [5, 6].

**3. Epidemiology**

**2. History**

2.8 million antibiotic-resistant infections occur in the US each year, and more than 35,000 people die as a result. Besides, 223,900 cases of *Clostridium difficile* occurred

Many bacteria produce important infections in human health, either due to community-acquired infections, nosocomial infections, or at intensive care units. Among these, many have an important phenotypic profile of antibiotic resistance. For example, *Staphylococcus aureus, Enterococcus* spp.*, Enterobacteriaceae* (other than *Salmonella* and *Shigella*), *Pseudomonas aeruginosa,* and *Acinetobacter* spp. [3, 4]. To classify these microorganisms according to the degree of resistance and acquired resistance profiles, a group of experts in the field of antimicrobial resistance in joint work with the European Center for the Prevention of Diseases and Control (ECDC) and the CDC established the definitions and characteristics among resistant bacteria: multidrug-resistant (MDR), extensively drug-resistant (XDR),

To establish objective parameters of the phenotypic resistance profile in each of these bacteria, epidemiologically significant antimicrobial categories were established. These categories were established based on the documents and cutoff points of the Clinical Laboratory Standards Institute (CLSI), the European Antimicrobial Sensitivity Testing Committee (EUCAST), and the US Food and

Based on the new limits and definitions: MDR bacteria possess acquired resistance to at least one antibiotic of three or more categories; XDR bacteria possess resistance to at least one antibiotic of almost all categories, except one or two of them; and PDR

Antimicrobial resistance has been observed in all families of antibiotics, includ-

The wide use of quinolones in clinical practice includes the administration of the antibiotic in prophylaxis, in neutropenic patients with cancers, in cirrhotic patients at risk for spontaneous bacterial peritonitis, and in urologic surgery, among others. In many of these cases, strains with varying degrees of resistance to quinolones have

In 1962, quinolones were discovered as an important treatment for various pathological manifestations. The first one was nalidixic acid, which was synthetically produced by George Lesher at the Sterling-Winthrop Research Institute. It was synthesized from the isolation of chloro-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acid years before, as a product derived from the synthesis of chloroquine [7]. Its origin dates back to the use of chloroquine as an antimalarial agent. It was until years after its development that nalidixic acid was approved for the treatment of urinary tract infections by Gram-negative bacteria. This compound does not have an important effect on Gram-positive bacteria, in addition to having a certain cytotoxic effect on the gastrointestinal tract and the central nervous system. Its effect on Gram-negative bacteria is characteristic of the first generation of quinolones [8].

The indiscriminate prescription of quinolones worldwide has led to a rapid increase in bacterial resistance. *Acinetobacter* spp., *Campylobacter* spp., *Capnocytophaga* spp., *Clostridium* spp.*, Escherichia coli, Klebsiella pneumoniae, Mycobacterium tuberculosis,* 

bacteria are resistant to all agents of all categories of antimicrobials [3, 4].

ing the latest generation and intrahospital antibiotics such as quinolones.

**26**

*Profile of resistance to quinolones of European countries (2015 vs. 2018).*

*Neisseria gonorrhea, Proteus mirabilis, P. aeruginosa, Salmonella* spp., *S. aureus,* and *Streptococcus pneumoniae,* among others, have been reported as resistant [7, 9, 10]*.*

The ECDC collects and reports through the European Antimicrobial Resistance Surveillance Network (EARS-Net) information of seven bacterial pathogens that commonly cause infections in humans: *Acinetobacter* spp., *Enterococcus faecalis, Enterococcus faecium*, *Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae,* and *Pseudomonas aeruginosa.* Information comparing their profile of resistance to quinolones in Europe between 2015 and 2018 can be found in **Table 1** [11, 12]*.*

## **4. The structure of quinolones**

The structure of quinolones derives from two types of rings, a naphthyridine core with a nitrogen molecule in positions 1 and 8. Through this structure, the compound is limited to being used as a therapy against Gram-negative bacteria. However, it has been shown that by inserting a cyclopropyl group in the first position of the nitrogen ring, an effect is achieved not only on Gram-negative bacteria but also on Gram-positive ones (**Figure 1**) [13, 14].

The second generation was developed in 1980, from the addition of a fluorine atom at position six, resulting in fluoroquinolones. These have higher activity in Gram-negative bacteria, as well as Gram-positive bacteria. Some fluoroquinolones can inhibit all Gram-negative organisms. Quinolones with piperazine on carbon 7 are effective in Gram-negative bacteria and the signaling of topoisomerase 4 (**Figure 1**) [13, 15–17].

Later, the third generation arises by adding certain molecules in the rings, such as the cyclopropyl ring in the first position of nitrogen, improving the activity in Gram-positive bacteria. Some of these modifications achieved sensitivity in organism resistant to different antibiotics, including *Streptococcus pneumoniae*. Other benefits of this generation are a longer life in serum and activity against anaerobic organisms (**Figure 1**) [7, 18, 19].

The fourth generation was later developed by incorporating nitrogen in the eighth position, resulting in a broad-spectrum antibiotic. Its action in some Grampositive organisms is more effective compared to the other generations; however, its activity in anaerobic organisms is limited. It has a superior bacterial selectivity to avoid a high level of resistance and its toxic effects are less unfavorable than in the other generations [7, 8]. Thanks to the modifications made to the quinolones,

#### **Figure 1.**

*Molecular structure of representative members of each quinolone generation. Based on PubChem public archive https://www.ncbi.nlm.nih.gov/pcsubstance [14, 17, 19, 20].*


*Adapted from: Pham TDM, Ziora ZM, Blaskovich MAT [7].*

#### **Table 2.**

*Classification of quinolones.*

an improvement in its pharmacokinetics and pharmacodynamics has been obtained, thus optimizing absorption, metabolism, and elimination, achieving lower toxicity and superiority in the mechanisms of action. It has also been possible to modify the half-life of the drug making only one dose per day necessary (**Figure 1**) [20].

**29**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

mechanism is topoisomerase mutations [15, 22].

incidence of hypersensitivity reactions [23, 24].

**5. Mechanism of action**

possess ATPase activity [30].

GyrA and GyrB, respectively [32].

**6. Resistance mechanisms**

of the drug).

of quinolones.

quinolones) [33].

based on three points (**Table 3**, **Figure 2**):

DNA replication [32].

It has been reported that several agents such as *Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae,* or *Staphylococcus aureus* have presented significant resistance to quinolones [21]. Plasmid-mediated quinolone resistance (PMQR) was a completely unexpected event since it was thought that the only mutation would occur in genes encoding topoisomerase II identification. Currently, the resistance mechanism is multifactorial. However, the most common quinolone resistance

The excessive use of this type of drug has caused the incidence rates of hypersensitivity to increase more and more, taking the second place of antibiotics with a greater number of hypersensitivity reactions in in-hospital patients. The main agents that cause hypersensitivity are ciprofloxacin, levofloxacin, and moxifloxacin. This has positioned quinolones as the non-beta-lactam antibiotics with the highest

The mechanism of action of quinolones is based on the inhibition of bacterial topoisomerases II and IV. Topoisomerases are enzymes responsible for maintaining the tertiary structure of DNA during various cellular processes, such as synthesis, replication, condensation, and decondensation of DNA, among others [25–29]. Topoisomerase II, also known as DNA gyrase, is considered a negative

supercoiling enzyme, which means that it cuts the two strands of DNA and propitiates that the DNA is twisted to the left producing a twist in a way contrary to the direction of the double helix. This enzyme participates in the DNA winding and relaxation during various processes, mainly in the synthesis and replication of DNA [30, 31]. The DNA gyrase consists of a heterotetramer, which is formed by two GyrA subunits and two GyrB subunits. The GyrA subunits participate in the union with the DNA and are responsible for making the double helix cuts. The GyrB subunits

Topoisomerase IV is responsible for preventing the chromatids from being chained, meaning it participates in the separation of daughter chromatids after

Like DNA gyrase, topoisomerase IV is made up of a tetramer. It has two ParC subunits and two ParE subunits. These subunits possess homologous activity of

When quinolones interact and inhibit topoisomerase II and IV, it induces DNA

To counteract the effect of quinolones, bacteria have developed various resistance mechanisms to these antibiotics. Bacterial resistance to quinolones is mainly

1.Chromosomal mutations in coding genes (mutations that alter the objectives

2.Mutations associated with the reduction of the intracytoplasmic concentration

3.PMQR genes (plasmids that protect cells from the lethal effects of

breakdown and cell death due to genotoxic damage [27–29].

Currently, nine fluoroquinolones have been approved in the US while others continue to be used in clinical trials. Information regarding the generations, compounds, and spectrum of activity can be found in **Table 2**.

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

*Antimicrobial Resistance - A One Health Perspective*

**28**

**Table 2.**

*Classification of quinolones.*

**Figure 1.**

an improvement in its pharmacokinetics and pharmacodynamics has been obtained, thus optimizing absorption, metabolism, and elimination, achieving lower toxicity and superiority in the mechanisms of action. It has also been possible to modify the half-life of the drug making only one dose per day necessary (**Figure 1**) [20]. Currently, nine fluoroquinolones have been approved in the US while others continue to be used in clinical trials. Information regarding the generations,

*Molecular structure of representative members of each quinolone generation. Based on PubChem public* 

1 Nalidixic acid Gram-negative bacteria (not *Pseudomonas* spp.)

Gram-negative bacteria and atypical pathogens (*Mycoplasma pneumoniae* and *Chlamydia pneumoniae*)

Gram-negative bacteria, Gram-positive bacteria (not *Streptococcus pneumoniae*), and atypical pathogens

Gram-negative bacteria, Gram-positive bacteria (*Streptococcus pneumoniae*) and improved activity

Gram-negative bacteria, Gram-positive bacteria (*Streptococcus pneumoniae*) and improved activity against atypical and anaerobic pathogens

against atypical pathogens

*archive https://www.ncbi.nlm.nih.gov/pcsubstance [14, 17, 19, 20].*

2 2a Ciprofloxacin, enoxacin, norfloxacin

3 Clinafloxacin, gatifloxacin,

4 Gatifloxacin, gemifloxacin,

*Adapted from: Pham TDM, Ziora ZM, Blaskovich MAT [7].*

2b Levofloxacin, lomefloxacin, ofloxacin

grepafloxacin, sparfloxacin.

moxifloxacin, trovafloxacinin

**Generation Compounds Activity spectrum**

compounds, and spectrum of activity can be found in **Table 2**.

It has been reported that several agents such as *Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae,* or *Staphylococcus aureus* have presented significant resistance to quinolones [21]. Plasmid-mediated quinolone resistance (PMQR) was a completely unexpected event since it was thought that the only mutation would occur in genes encoding topoisomerase II identification. Currently, the resistance mechanism is multifactorial. However, the most common quinolone resistance mechanism is topoisomerase mutations [15, 22].

The excessive use of this type of drug has caused the incidence rates of hypersensitivity to increase more and more, taking the second place of antibiotics with a greater number of hypersensitivity reactions in in-hospital patients. The main agents that cause hypersensitivity are ciprofloxacin, levofloxacin, and moxifloxacin. This has positioned quinolones as the non-beta-lactam antibiotics with the highest incidence of hypersensitivity reactions [23, 24].

#### **5. Mechanism of action**

The mechanism of action of quinolones is based on the inhibition of bacterial topoisomerases II and IV. Topoisomerases are enzymes responsible for maintaining the tertiary structure of DNA during various cellular processes, such as synthesis, replication, condensation, and decondensation of DNA, among others [25–29].

Topoisomerase II, also known as DNA gyrase, is considered a negative supercoiling enzyme, which means that it cuts the two strands of DNA and propitiates that the DNA is twisted to the left producing a twist in a way contrary to the direction of the double helix. This enzyme participates in the DNA winding and relaxation during various processes, mainly in the synthesis and replication of DNA [30, 31].

The DNA gyrase consists of a heterotetramer, which is formed by two GyrA subunits and two GyrB subunits. The GyrA subunits participate in the union with the DNA and are responsible for making the double helix cuts. The GyrB subunits possess ATPase activity [30].

Topoisomerase IV is responsible for preventing the chromatids from being chained, meaning it participates in the separation of daughter chromatids after DNA replication [32].

Like DNA gyrase, topoisomerase IV is made up of a tetramer. It has two ParC subunits and two ParE subunits. These subunits possess homologous activity of GyrA and GyrB, respectively [32].

When quinolones interact and inhibit topoisomerase II and IV, it induces DNA breakdown and cell death due to genotoxic damage [27–29].

#### **6. Resistance mechanisms**

To counteract the effect of quinolones, bacteria have developed various resistance mechanisms to these antibiotics. Bacterial resistance to quinolones is mainly based on three points (**Table 3**, **Figure 2**):



*Adapted from: Álvarez-Hernández DA, Garza-Mayén GS, Vázquez-López R. Quinolones. Nowadays perspectives and mechanisms of resistance [34].*

#### **Table 3.**

*Mechanisms of resistance to quinolones.*

#### **6.1 Chromosomal mutations in coding genes (mutations that alter the objectives of the drug)**

The quinolone resistance associated with chromosomal mutations occurs due to errors in the replication of the genes encoding the GyrA subunits of DNA gyrase and ParC of topoisomerase IV [33, 35].

In the amino acid sequences of the GyrA and ParC subunits, there are specific regions that interact with the DNA. In these regions, there are conserved domains called quinolone resistance determining region (QRDR) [31, 35–39].

It is precisely in the sequences that code for each of the QRDR domains of the GyrA and ParC subunit genes, where such mutations occur [31, 35–39].

It has been reported that quinolone resistance may also occur due to mutations in the genes encoding the GyrB and ParE subunits; however, they do not occur so frequently and their clinical value appears to be very limited [35, 40, 41].

There is evidence that in Gram-negative bacteria, DNA gyrase turns out to be more susceptible to inhibition than topoisomerase IV. On the other hand, in Grampositive bacteria, the opposite phenomenon occurs; that is, that topoisomerase IV is more susceptible to inhibition than gyrase. However, certain bacteria show the opposite effect, being the exception to the rule [31, 42, 43].

Therefore, we can affirm that the phenomenon of resistance in the majority of Gram-negative bacteria occurs mainly in GyrA, while in most Gram-positive bacteria the inhibition of ParC is the most important [31, 42, 43].

Summarizing, mutations that occur in the sequences encoding the QRDR domains in both GyrA*-*ParC and GyrB*-*ParE favor a decrease in the binding affinity of quinolones with the DNA–DNA gyrase and DNA-topoisomerase IV complex [33, 35].

**31**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

**concentration of quinolones**

3.A combination of both mechanisms.

participates in this type of bacteria [44].

the bacterial cell.

**Figure 2.**

*et al. [22].*

porin synthesis [35, 46].

**6.2 Mutations associated with the reduction of the intracytoplasmic** 

decrease in concentration is determined by certain mutations. This phenomenon is achieved through three mechanisms:

2.Decreased membrane permeability toward the antibiotic.

Another important quinolone resistance mechanism consists in the ability of the bacteria to decrease the intracytoplasmic concentration of the antibiotic; this

*Schematic representation of the mechanisms of bacterial resistance to quinolones. Based on Susana Correia* 

1.Efflux pumps that promote the active transport of quinolones to the outside of

It has been described that only efflux pumps participate in Gram-positive bacteria as mechanisms to reduce the intracytoplasmic concentration of quinolones since there is no evidence that the decrease in cytoplasmic membrane permeability

On the other hand, Gram-negative bacteria do have both mechanisms and participate in a complementary way with one another, the decrease in permeability in the cytoplasmic membrane being the most important for these bacteria [45].

These two mechanisms involved in the decrease of the intracytoplasmic concentration of quinolones are not induced by the drugs themselves. There is evidence that these two mechanisms occur because of mutations in genes that encode regulatory proteins that control transcription of the outflow pump or genes that code for

**Figure 2.**

*Antimicrobial Resistance - A One Health Perspective*

**Mechanism Description**

Chromosomal mutations in coding

Mutations associated with the reduction of the intracytoplasmic concentration of quinolones

Plasmid-mediated quinolone resistance

genes

genes

**Table 3.**

**6.1 Chromosomal mutations in coding genes (mutations that alter the objectives** 

*Adapted from: Álvarez-Hernández DA, Garza-Mayén GS, Vázquez-López R. Quinolones. Nowadays perspectives* 

Occurs due to errors in the replication of the genes encoding the GyrA subunits

Occurs due to the activation of plasmid-mediated quinolone resistance genes.

AAC(6′)-lb-cr acetylates quinolones with an appropriate amino nitrogen target

Both Reduction of the

proteins

membrane permeability by downregulation of extra-membrane

QepA and OqxAB, which increase the outflow of quinolones through efflux pumps

Occurs due to mutations that lead to a decrease in the intracytoplasmic

of DNA gyrase and ParC of topoisomerase IV

Overexpression of efflux pumps from the resistance-nodulation-cell

Among them are:

Qnr's encode proteins that protect DNA gyrase and topoisomerase IV

division

concentration of the antibiotic. It may happen through:

The quinolone resistance associated with chromosomal mutations occurs due to errors in the replication of the genes encoding the GyrA subunits of DNA gyrase

In the amino acid sequences of the GyrA and ParC subunits, there are specific regions that interact with the DNA. In these regions, there are conserved domains

It is precisely in the sequences that code for each of the QRDR domains of the

It has been reported that quinolone resistance may also occur due to mutations in the genes encoding the GyrB and ParE subunits; however, they do not occur so

There is evidence that in Gram-negative bacteria, DNA gyrase turns out to be more susceptible to inhibition than topoisomerase IV. On the other hand, in Grampositive bacteria, the opposite phenomenon occurs; that is, that topoisomerase IV is more susceptible to inhibition than gyrase. However, certain bacteria show the

Therefore, we can affirm that the phenomenon of resistance in the majority of Gram-negative bacteria occurs mainly in GyrA, while in most Gram-positive

Summarizing, mutations that occur in the sequences encoding the QRDR domains in both GyrA*-*ParC and GyrB*-*ParE favor a decrease in the binding affinity of quinolones with the DNA–DNA gyrase and DNA-topoisomerase

called quinolone resistance determining region (QRDR) [31, 35–39].

GyrA and ParC subunit genes, where such mutations occur [31, 35–39].

frequently and their clinical value appears to be very limited [35, 40, 41].

opposite effect, being the exception to the rule [31, 42, 43].

bacteria the inhibition of ParC is the most important [31, 42, 43].

**30**

IV complex [33, 35].

**of the drug)**

*and mechanisms of resistance [34].*

*Mechanisms of resistance to quinolones.*

and ParC of topoisomerase IV [33, 35].

*Schematic representation of the mechanisms of bacterial resistance to quinolones. Based on Susana Correia et al. [22].*

## **6.2 Mutations associated with the reduction of the intracytoplasmic concentration of quinolones**

Another important quinolone resistance mechanism consists in the ability of the bacteria to decrease the intracytoplasmic concentration of the antibiotic; this decrease in concentration is determined by certain mutations.

This phenomenon is achieved through three mechanisms:


It has been described that only efflux pumps participate in Gram-positive bacteria as mechanisms to reduce the intracytoplasmic concentration of quinolones since there is no evidence that the decrease in cytoplasmic membrane permeability participates in this type of bacteria [44].

On the other hand, Gram-negative bacteria do have both mechanisms and participate in a complementary way with one another, the decrease in permeability in the cytoplasmic membrane being the most important for these bacteria [45].

These two mechanisms involved in the decrease of the intracytoplasmic concentration of quinolones are not induced by the drugs themselves. There is evidence that these two mechanisms occur because of mutations in genes that encode regulatory proteins that control transcription of the outflow pump or genes that code for porin synthesis [35, 46].

*6.2.1 Mutations associated with the reduction of the intracytoplasmic concentration of quinolones in Gram-positive bacteria*

This resistance mechanism in Gram-positive bacteria is associated with the presence of chromosomally encoded efflux pumps that decrease the intracytoplasmic concentration of the antibiotic, giving the bacteria the characteristic of being MDR.

Efflux pumps are classified into two groups: primary active transporters and secondary active transporters [47].

The primary active transporter proteins are pumps that use ATP as a source of energy. This type of primary active transporter integrates the members of the ATPbinding cassette (ABC) superfamily [48–50].

On the other hand, the secondary active transporter proteins use the energy obtained by the difference of chemical gradients formed by either protons or ions, for example, sodium ions [48, 49].

Four types of secondary active transporter proteins have been identified: [47–49].


#### *6.2.1.1 SMR (the small multidrug-resistance family)*

Members of this family are proteins made up of an antiparallel dimer. Each monomer of this dimer has four transmembrane helices (TM1, TM2, TM3, and TM4). The TM 1 to M3 helices comprise the substrate binding pocket, while each TM4 helix is responsible for SMR TM4-TM4 dimerization [51–53].

The members of the SMR family are associated with resistance to various toxic compounds and some antibiotics; however, they do not appear to play a relevant role in resistance to quinolones.

#### *6.2.1.2 MFS (the major facilitator superfamily)*

Concerning efflux pumps related to the intracytoplasmic decrease in quinolone and consequently linked to resistance to this drug, they are efflux pumps that are part of the MFS. Three members of this family associated with quinolone resistance have been identified: NorA*,* NorB [50], and NorC [54]. Overexpression of each of three efflux pumps increases resistance to quinolones four to eight times [33].

#### *6.2.1.2.1 NorA*

The chromosomal gene that codes for NorA could be identified in 1986 from the isolation of *Staphylococcus aureus* obtained from a urine sample from a patient who had received treatment with norfloxacin at Teikyo University Hospital Japan [55]. It has been observed that NorA participates in the pumping of various quinolones, mainly ciprofloxacin and norfloxacin [56, 57].

Subsequent studies of genetic diversity described three alleles for the *NorA* gene [58]: *NorAI* (Yoshida), *NorAII* (Noguchi), and *NorAIII* (Kaatz). A correlation has been observed between the different types of NorA alleles

**33**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

pathophysiology of certain infections [59].

is regulated negatively by MgrA [54].

bacterium [58].

*6.2.1.2.2 NorB*

*6.2.1.2.3 NorC*

[54, 60–62].

*6.2.1.3.1 MdeA*

norfloxacin [67, 68].

and specific lineages of *S. aureus*. This fact suggests that there is a correlation between the NorA variants and the population structure (lineages) of this

It has been described that the expression of the efflux pump NorB gives certain

The efflux pump *Norc* enhances the exit of quinolones such as ciprofloxacin, garenoxacin moxifloxacin, and sparfloxacin out of the bacterial cell. Its expression

Many regulatory proteins participate in a complex regulatory process in the gene expression of NorA, NorB, and NorC. One of these regulatory proteins is MgrA, which shows the ability to bind to the NorA promoter region. The overexpression of MgrA causes the inhibition of the expression of NorA, NorB, and NorC, in the opposite, resistance to quinolones is associated with a low activity of *MgrA* and the consequent overproduction of NorA, NorB, and NorC that will promote a decrease in the intracytoplasmic concentration of the drug

There is evidence that MgrA activity could be determined by environmental conditions in which the bacterium is found. Acid conditions, oxidative, as well as the presence of iron, could alter the activity of MgrA and consequently the expression of NorA, NorB, and NorC and its effect on the pumping of quinolone and its

On the other hand, another transcriptional regulator, called NorG, which activates the expression of NorA and NorB but suppresses the expression of NorC, has been described. It is important to understand that the regulation of the gene expression of *NorA*, *NorB*, and *NorC* results from a complex molecular framework where both activators and inhibitors participate and the balance between them, as well as the environmental and nutritional conditions in which the bacteria develops, will give as a result the resistance or the lack of it to quinolones [35, 61, 62, 66].

*MdeA* gen was identified in an open reading frame (ORF) expression library of the *S. aureus* genome. The efflux pump protein MdeA belongs to the MFS using the

MdeA confers resistance to the biocides benzalkonium chloride, dequalinium,

concentration in the bacterial cytoplasm [35, 59, 63–65].

*6.2.1.3 Other members of the MFS (major facilitator superfamily)*

proton motive force to energize the transport of its substrates [67, 68].

tetraphenylphosphonium, and to the dye ethidium bromide [67]. MdeA also confers resistance to multiple antibiotics among which are fusidic acid, mupirocin, novobiocin, and virginiamycin, and to some extent toward ciprofloxacin and

bacteria (e.g., *Staphylococcus aureus*) the adaptability in tissue infection conditions, even in the absence of antibiotics. This fact occurs because NorB gives *Staphylococcus aureus* the ability to eliminate antibacterial substances present in the abscess and produced as a defense mechanism by the host. In this way, NorB not only participates in the quinolone resistance mechanism but also contributes to the and specific lineages of *S. aureus*. This fact suggests that there is a correlation between the NorA variants and the population structure (lineages) of this bacterium [58].

#### *6.2.1.2.2 NorB*

*Antimicrobial Resistance - A One Health Perspective*

secondary active transporters [47].

for example, sodium ions [48, 49].

role in resistance to quinolones.

[47–49].

binding cassette (ABC) superfamily [48–50].

1.The small multidrug-resistance (SMR) family

3.Multidrug and toxic compound extrusion (MATE) family

4.The resistance-nodulation-cell division (RND) superfamily.

TM4 helix is responsible for SMR TM4-TM4 dimerization [51–53].

2.The major facilitator superfamily (MFS)

*6.2.1.1 SMR (the small multidrug-resistance family)*

*6.2.1.2 MFS (the major facilitator superfamily)*

mainly ciprofloxacin and norfloxacin [56, 57].

*6.2.1 Mutations associated with the reduction of the intracytoplasmic concentration of quinolones in Gram-positive bacteria*

This resistance mechanism in Gram-positive bacteria is associated with the presence of chromosomally encoded efflux pumps that decrease the intracytoplasmic concentration of the antibiotic, giving the bacteria the characteristic of being MDR. Efflux pumps are classified into two groups: primary active transporters and

The primary active transporter proteins are pumps that use ATP as a source of energy. This type of primary active transporter integrates the members of the ATP-

On the other hand, the secondary active transporter proteins use the energy obtained by the difference of chemical gradients formed by either protons or ions,

Four types of secondary active transporter proteins have been identified:

Members of this family are proteins made up of an antiparallel dimer. Each monomer of this dimer has four transmembrane helices (TM1, TM2, TM3, and TM4). The TM 1 to M3 helices comprise the substrate binding pocket, while each

The members of the SMR family are associated with resistance to various toxic compounds and some antibiotics; however, they do not appear to play a relevant

Concerning efflux pumps related to the intracytoplasmic decrease in quinolone and consequently linked to resistance to this drug, they are efflux pumps that are part of the MFS. Three members of this family associated with quinolone resistance have been identified: NorA*,* NorB [50], and NorC [54]. Overexpression of each of three efflux pumps increases resistance to quinolones four to eight times [33].

The chromosomal gene that codes for NorA could be identified in 1986 from the isolation of *Staphylococcus aureus* obtained from a urine sample from a patient who had received treatment with norfloxacin at Teikyo University Hospital Japan [55]. It has been observed that NorA participates in the pumping of various quinolones,

Subsequent studies of genetic diversity described three alleles for the *NorA* gene [58]: *NorAI* (Yoshida), *NorAII* (Noguchi), and *NorAIII* (Kaatz). A correlation has been observed between the different types of NorA alleles

**32**

*6.2.1.2.1 NorA*

It has been described that the expression of the efflux pump NorB gives certain bacteria (e.g., *Staphylococcus aureus*) the adaptability in tissue infection conditions, even in the absence of antibiotics. This fact occurs because NorB gives *Staphylococcus aureus* the ability to eliminate antibacterial substances present in the abscess and produced as a defense mechanism by the host. In this way, NorB not only participates in the quinolone resistance mechanism but also contributes to the pathophysiology of certain infections [59].

#### *6.2.1.2.3 NorC*

The efflux pump *Norc* enhances the exit of quinolones such as ciprofloxacin, garenoxacin moxifloxacin, and sparfloxacin out of the bacterial cell. Its expression is regulated negatively by MgrA [54].

Many regulatory proteins participate in a complex regulatory process in the gene expression of NorA, NorB, and NorC. One of these regulatory proteins is MgrA, which shows the ability to bind to the NorA promoter region. The overexpression of MgrA causes the inhibition of the expression of NorA, NorB, and NorC, in the opposite, resistance to quinolones is associated with a low activity of *MgrA* and the consequent overproduction of NorA, NorB, and NorC that will promote a decrease in the intracytoplasmic concentration of the drug [54, 60–62].

There is evidence that MgrA activity could be determined by environmental conditions in which the bacterium is found. Acid conditions, oxidative, as well as the presence of iron, could alter the activity of MgrA and consequently the expression of NorA, NorB, and NorC and its effect on the pumping of quinolone and its concentration in the bacterial cytoplasm [35, 59, 63–65].

On the other hand, another transcriptional regulator, called NorG, which activates the expression of NorA and NorB but suppresses the expression of NorC, has been described. It is important to understand that the regulation of the gene expression of *NorA*, *NorB*, and *NorC* results from a complex molecular framework where both activators and inhibitors participate and the balance between them, as well as the environmental and nutritional conditions in which the bacteria develops, will give as a result the resistance or the lack of it to quinolones [35, 61, 62, 66].

#### *6.2.1.3 Other members of the MFS (major facilitator superfamily)*

#### *6.2.1.3.1 MdeA*

*MdeA* gen was identified in an open reading frame (ORF) expression library of the *S. aureus* genome. The efflux pump protein MdeA belongs to the MFS using the proton motive force to energize the transport of its substrates [67, 68].

MdeA confers resistance to the biocides benzalkonium chloride, dequalinium, tetraphenylphosphonium, and to the dye ethidium bromide [67]. MdeA also confers resistance to multiple antibiotics among which are fusidic acid, mupirocin, novobiocin, and virginiamycin, and to some extent toward ciprofloxacin and norfloxacin [67, 68].

#### *6.2.1.3.2 SdrM*

In 2006 Yamada et al. cloned a new gene called *SA1972* isolated from *Staphylococcus aureus*. The product obtained was called SdrM and it was proven that it conferred resistance to the bacteria against, acriflavine, ethidium bromide, and norfloxacin. SdrM was classified as an efflux pump belonging to the MFS [69].

## *6.2.1.3.3 QacB (III)*

The *qacA* and *qacB* genes that code for efflux pump proteins (QacA and QacB, respectively) are present in methicillin-resistant *Staphylococcus aureus* (MRSA). The efflux pump QacA has two isoforms, while the pump QacB has four known as QacBI, QacBII, QacBIII, and QacBIV. It has been observed that the QacBIII variant confers resistance to *S. aureus* to fluoroquinolones [70].

#### *6.2.1.4 MATE (multidrug and toxic compound extrusion family)*

#### *6.2.1.4.1 MepA*

The efflux pump MepA belongs to the multidrug and toxic compound extrusion (MATE) family. MepA gives the bacterium a phenotypic MDR profile associated with low-level resistance to some quaternary ammonium compounds. It also confers resistance to certain antibiotics, mainly toward glycylcyclines and to a lesser extent resistance to ciprofloxacin and norfloxacin [71–73].

In addition to the efflux pump described above, there are other transporters in Gram-positive bacteria that participate in the decrease in the intracytoplasmic concentration of quinolones in the bacterial cell, participating in resistance to this drug. Some of these transporters are LmrS, Bmr, Bmr3 and Blt, PmrA66, LmrP67, PatAB69, SatAB70, LmrA71, FepA, FepR, and TetR [35].

### *6.2.2 Mutations associated with the reduction of concentration in Gram-negative bacteria*

#### *6.2.2.1 RND (resistance-nodulation-cell division superfamily)*

Gram-negative bacteria use efflux pumps belonging to the RND superfamily as the main mechanism of resistance to quinolones. The efflux pump RND pumps are a molecular complex consisting of three elements (**Figure 3**) [49, 74–77]:


The adapter protein MFP links the pump RND and the OMF protein [49, 74–77]. In *E. coli*, the presence of five RND efflux transporters has been reported:

**35**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

4.MdtABC [83, 84]

*Based on Eun-Hae Kim et al. [77].*

**Figure 3.**

5.MdtEF [85, 86]

elements [75, 87]:

*6.2.2.2 AcrAB-TolC [acriflavine (Acr) efflux system]*

is no known effect on quinolone resistance [80, 90].

1.The outer-membrane channel TolC

membrane proteins

lone molecules [88, 89].

*6.2.2.2.1 AcrAD*

*6.2.2.2.2 AcrEF*

quinolones, and penams [91, 92].

The AcrAB-TolC or acriflavine (Acr) efflux system consists of three

*Schematic representation of molecular structure of RND (resistance-nodulation-cell division superfamily).* 

3.In the inner membrane is the secondary transporter AcrB.

2.In the periplasmic space is the AcrA protein, which bridges these two integral

There is evidence that the ratio between the proteins that make up this complex is 3: 6: 3, comprising an AcrB trimer, an AcrA hexamer, and a TolC trimer [75, 87]. It has been shown that various dyes can be accommodated in the transmembrane domain of the Acr efflux system, as well as doxorubicin, minocycline, and quino-

AcrAD is an antibiotic efflux pump complex of the RND type. It provides resistance to aminoglycosides such as amikacin, gentamicin, and tobramycin. There

AcrEF is an antibiotic efflux pump complex of the resistance-nodulation-cell division (RND) type. It provides resistance to cephalosporins, cephamycins, fluoro-


*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

#### **Figure 3.**

*Antimicrobial Resistance - A One Health Perspective*

confers resistance to *S. aureus* to fluoroquinolones [70].

resistance to ciprofloxacin and norfloxacin [71–73].

SatAB70, LmrA71, FepA, FepR, and TetR [35].

*6.2.2.1 RND (resistance-nodulation-cell division superfamily)*

1.In the inner membrane is RND pump protein.

ing to the outer membrane factor (OMF) family.

the periplasmic space.

1.AcrAB [78, 79]

2.AcrAD [80, 81]

3.AcrEF [82]

*6.2.1.4 MATE (multidrug and toxic compound extrusion family)*

In 2006 Yamada et al. cloned a new gene called *SA1972* isolated from

*Staphylococcus aureus*. The product obtained was called SdrM and it was proven that it conferred resistance to the bacteria against, acriflavine, ethidium bromide, and norfloxacin. SdrM was classified as an efflux pump belonging to the MFS [69].

The *qacA* and *qacB* genes that code for efflux pump proteins (QacA and QacB, respectively) are present in methicillin-resistant *Staphylococcus aureus* (MRSA). The efflux pump QacA has two isoforms, while the pump QacB has four known as QacBI, QacBII, QacBIII, and QacBIV. It has been observed that the QacBIII variant

The efflux pump MepA belongs to the multidrug and toxic compound extrusion (MATE) family. MepA gives the bacterium a phenotypic MDR profile associated with low-level resistance to some quaternary ammonium compounds. It also confers resistance to certain antibiotics, mainly toward glycylcyclines and to a lesser extent

In addition to the efflux pump described above, there are other transporters in Gram-positive bacteria that participate in the decrease in the intracytoplasmic concentration of quinolones in the bacterial cell, participating in resistance to this drug. Some of these transporters are LmrS, Bmr, Bmr3 and Blt, PmrA66, LmrP67, PatAB69,

Gram-negative bacteria use efflux pumps belonging to the RND superfamily as the main mechanism of resistance to quinolones. The efflux pump RND pumps are

2.An adapter protein from the MFP (membrane fusion protein) family located in

3.In the outer membrane is an outer membrane channel protein (OMP) belong-

The adapter protein MFP links the pump RND and the OMF protein [49, 74–77]. In *E. coli*, the presence of five RND efflux transporters has been reported:

*6.2.2 Mutations associated with the reduction of concentration in Gram-negative* 

a molecular complex consisting of three elements (**Figure 3**) [49, 74–77]:

*6.2.1.3.2 SdrM*

*6.2.1.3.3 QacB (III)*

*6.2.1.4.1 MepA*

*bacteria*

**34**

*Schematic representation of molecular structure of RND (resistance-nodulation-cell division superfamily). Based on Eun-Hae Kim et al. [77].*

4.MdtABC [83, 84]

5.MdtEF [85, 86]

*6.2.2.2 AcrAB-TolC [acriflavine (Acr) efflux system]*

The AcrAB-TolC or acriflavine (Acr) efflux system consists of three elements [75, 87]:

1.The outer-membrane channel TolC

2.In the periplasmic space is the AcrA protein, which bridges these two integral membrane proteins

3.In the inner membrane is the secondary transporter AcrB.

There is evidence that the ratio between the proteins that make up this complex is 3: 6: 3, comprising an AcrB trimer, an AcrA hexamer, and a TolC trimer [75, 87].

It has been shown that various dyes can be accommodated in the transmembrane domain of the Acr efflux system, as well as doxorubicin, minocycline, and quinolone molecules [88, 89].

*6.2.2.2.1 AcrAD*

AcrAD is an antibiotic efflux pump complex of the RND type. It provides resistance to aminoglycosides such as amikacin, gentamicin, and tobramycin. There is no known effect on quinolone resistance [80, 90].

#### *6.2.2.2.2 AcrEF*

AcrEF is an antibiotic efflux pump complex of the resistance-nodulation-cell division (RND) type. It provides resistance to cephalosporins, cephamycins, fluoroquinolones, and penams [91, 92].

## *6.2.2.2.3 MdtABC*

MdtABC is an antibiotic efflux pump complex of the resistance-nodulationcell division (RND) type. It provides resistance to aminocoumarins, which have a mechanism of action similar to quinolones [93, 94].

## *6.2.2.2.4 MdtEF*

MdtEF is an antibiotic efflux pump complex of the RND type. It provides resistance to fluoroquinolones, macrolides, and penams [82].

### *6.2.2.3 Other members of the RND (resistance-nodulation-cell division superfamily)*

#### *6.2.2.3.1 MexAB-OprM efflux system*

MexAB-OprM efflux system is an antibiotic efflux pump complex of the RND type. It provides resistance to multiple antibiotics, including aminocoumarins, carbapenems, cephalosporins, cephamycins, diaminopyrimidines, fluoroquinolones, macrolides, monobactams, penams, phenicols, peptides, sulfonamides, and tetracyclines [95, 96].

#### *6.2.2.3.2 MexCD-OprJ with type A NfxB mutation*

MexCD-OprJ with type A NfxB mutation is an antibiotic efflux pump complex of the RND type. It provides resistance to the aminocoumarins, cephalosporins, diaminopyrimidines, fluoroquinolones, macrolides, penams, phenicols, and tetracyclines [97].

#### *6.2.2.3.3 MexCD-OprJ with type B NfxB mutation*

MexCD-OprJ with type B NfxB mutation is an antibiotic efflux pump complex of the RND type. It provides resistance to the aminocoumarins, aminoglycosides, cephalosporins, diaminopyrimidines, fluoroquinolones, macrolides, penams, phenicols, and tetracyclines [97].

#### *6.2.2.3.4 MexEF-OprN*

MexEF-OprN is an antibiotic efflux pump complex RND. It provides resistance to diaminopyrimidines, fluoroquinolones, and phenicols [98].

#### *6.2.2.3.5 MexXY-OprM*

MexXY-OprM is an antibiotic efflux pump complex RND. It provides resistance to the acridine dye, aminoglycosides, carbapenems, cephalosporins, cephamycins, fluoroquinolones, macrolides, penams, phenicols, and tetracyclines [96, 99, 100].

#### *6.2.2.3.6 CmeABC*

CmeABC is an antibiotic efflux pump complex RND. It provides resistance to cephalosporins, fluoroquinolones, fusidic acid, and macrolides [101, 102].

**37**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

glycylcyclines and tetracyclines [104, 105].

quinolones and tetracyclines [106].

AdeIJK is an antibiotic efflux pump complex RND. It provides resistance to carbapenems, cephalosporins, diaminopyrimidines, fluoroquinolones, lincosamides,

AdeABC is an antibiotic efflux pump complex RND. It provides resistance to

AdeL is an antibiotic efflux pump complex RND. It provides resistance to fluoro-

SmeDEF is an antibiotic efflux pump complex RND. It provides resistance to

Other molecular complexes associated with decreasing the intracytoplasmic

EmrAB-TolC is an antibiotic efflux pump belonging to MFS. It provides resis-

MdfA is an antibiotic efflux pump belonging to MFS. It provides resistance to benzalkonium chloride, fluoroquinolones, rhodamine, and tetracyclines [109, 110].

Other molecular complexes associated with decreasing the intracytoplasmic

The OprF porin channel is permeable to quinolones and other antibiotics, promoting its outflow and decreasing intracytoplasmic concentration and conse-

**6.3 Plasmid-mediated quinolone resistance genes (plasmids that protect cells** 

In 1998 at the University of Alabama, from the isolation of *Klebsiella pneumoniae* from a urine sample, Martinez et al. managed to identify a plasmid they named *pMG252*. They demonstrated that this plasmid induced bacterial resistance to

quently is a mechanism of antibiotic resistance for the bacteria [111, 112].

*6.2.2.4 Members of the MFS (major facilitator superfamily) in Gram-negative* 

macrolides, penems, phenicols, rifamycins, and tetracyclines [103].

fluoroquinolones, macrolides, phenicols, and tetracyclines [107].

concentration of antibiotics in Gram-negative bacteria include:

concentration of antibiotics in Gram-negative bacteria include:

*6.2.2.3.7 AdeIJK*

*6.2.2.3.8 AdeABC*

*6.2.2.3.9 AdeL*

*6.2.2.3.10 SmeDEF*

*bacteria*

*6.2.2.4.1 EmrAB-TolC*

*6.2.2.4.2 MdfA*

*6.2.2.5.1 Porin OprF*

tance to fluoroquinolones [108].

*6.2.2.5 Other Gram-negative mechanisms*

**from the lethal effects of quinolones)**

*Mechanisms of Resistance to Quinolones DOI: http://dx.doi.org/10.5772/intechopen.92577*

### *6.2.2.3.7 AdeIJK*

*Antimicrobial Resistance - A One Health Perspective*

mechanism of action similar to quinolones [93, 94].

resistance to fluoroquinolones, macrolides, and penams [82].

*6.2.2.3 Other members of the RND (resistance-nodulation-cell division* 

MdtABC is an antibiotic efflux pump complex of the resistance-nodulationcell division (RND) type. It provides resistance to aminocoumarins, which have a

MdtEF is an antibiotic efflux pump complex of the RND type. It provides

MexAB-OprM efflux system is an antibiotic efflux pump complex of the RND type. It provides resistance to multiple antibiotics, including aminocoumarins, carbapenems, cephalosporins, cephamycins, diaminopyrimidines, fluoroquinolones, macrolides, monobactams, penams, phenicols, peptides, sulfonamides, and

MexCD-OprJ with type A NfxB mutation is an antibiotic efflux pump complex of the RND type. It provides resistance to the aminocoumarins, cephalosporins, diaminopyrimidines, fluoroquinolones, macrolides, penams, phenicols, and

MexCD-OprJ with type B NfxB mutation is an antibiotic efflux pump complex of the RND type. It provides resistance to the aminocoumarins, aminoglycosides, cephalosporins, diaminopyrimidines, fluoroquinolones, macrolides, penams,

MexEF-OprN is an antibiotic efflux pump complex RND. It provides resistance

MexXY-OprM is an antibiotic efflux pump complex RND. It provides resistance to the acridine dye, aminoglycosides, carbapenems, cephalosporins,

cephamycins, fluoroquinolones, macrolides, penams, phenicols, and tetracyclines

CmeABC is an antibiotic efflux pump complex RND. It provides resistance to

cephalosporins, fluoroquinolones, fusidic acid, and macrolides [101, 102].

*6.2.2.2.3 MdtABC*

*6.2.2.2.4 MdtEF*

*superfamily)*

tetracyclines [95, 96].

tetracyclines [97].

*6.2.2.3.1 MexAB-OprM efflux system*

*6.2.2.3.2 MexCD-OprJ with type A NfxB mutation*

*6.2.2.3.3 MexCD-OprJ with type B NfxB mutation*

to diaminopyrimidines, fluoroquinolones, and phenicols [98].

phenicols, and tetracyclines [97].

*6.2.2.3.4 MexEF-OprN*

*6.2.2.3.5 MexXY-OprM*

[96, 99, 100].

*6.2.2.3.6 CmeABC*

**36**

AdeIJK is an antibiotic efflux pump complex RND. It provides resistance to carbapenems, cephalosporins, diaminopyrimidines, fluoroquinolones, lincosamides, macrolides, penems, phenicols, rifamycins, and tetracyclines [103].

#### *6.2.2.3.8 AdeABC*

AdeABC is an antibiotic efflux pump complex RND. It provides resistance to glycylcyclines and tetracyclines [104, 105].
