*6.2.2.3.9 AdeL*

AdeL is an antibiotic efflux pump complex RND. It provides resistance to fluoroquinolones and tetracyclines [106].

## *6.2.2.3.10 SmeDEF*

SmeDEF is an antibiotic efflux pump complex RND. It provides resistance to fluoroquinolones, macrolides, phenicols, and tetracyclines [107].

Other molecular complexes associated with decreasing the intracytoplasmic concentration of antibiotics in Gram-negative bacteria include:

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

## *6.2.2.4.1 EmrAB-TolC*

EmrAB-TolC is an antibiotic efflux pump belonging to MFS. It provides resistance to fluoroquinolones [108].

#### *6.2.2.4.2 MdfA*

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

#### *6.2.2.5 Other Gram-negative mechanisms*

Other molecular complexes associated with decreasing the intracytoplasmic concentration of antibiotics in Gram-negative bacteria include:

## *6.2.2.5.1 Porin OprF*

The OprF porin channel is permeable to quinolones and other antibiotics, promoting its outflow and decreasing intracytoplasmic concentration and consequently is a mechanism of antibiotic resistance for the bacteria [111, 112].

#### **6.3 Plasmid-mediated quinolone resistance genes (plasmids that protect cells from the lethal effects of quinolones)**

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

fluoroquinines and nalidixic acid. This resistance phenomenon could be induced in a variety of bacteria deficient in outer-membrane porins. They also described that this plasmid promoted the acceleration of resistance development and its propagation. The gene responsible for this resistance was called *qnr*, later it became *qnrA* [113, 114].

In 2002, Tran and Jacoby, working with the qnr plasmid, managed to identify an integron-like environment upstream from qacEΔ1 and sulI. The product obtained from this gene was a 218-aa protein called QnrA. This protein belonging to the pentapeptide repeat family shared sequence homology with the immunity protein McbG. Previous studies suggested that McbG protects DNA gyrase from the action of various genotoxic chemicals [115].

Based on the mechanism of action of quinolones (the inhibition of topoisomerases I and IV) and the similarity of QnrA to McbG, Tran and Jacoby determined the ability of QnrA to induce resistance against quinolones by topoisomerase protection [115].

In 2005, two independent teams managed to determine the same activity as QnrA for two other proteins identified as QnrB [116] and QnrS [117].

Subsequent studies of the qnrA plasmid found that this plasmid was able to promote greater resistance than expected and that is how, in 2006, Ari Robicsek et al. discovered another mechanism of action of resistance to quinolones mediated by the enzymatic action of aminoglycoside acetyltransferase, AAC(6′)-Ib-cr. They also reported that the quinolone resistance mechanism was determined by reduction of the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent [118].

In 2007, three groups of researchers separately demonstrated another resistance mechanism encoded by plasmids. These works, in correlation with Martinez's works, involve quinolone efflux pumps mediated by plasmids QepA [119, 120] and OqxAB [121].

In summary, there are three mechanisms for PMQR:


#### **7. Concluding remarks**

Bacterial resistance to antibiotics is a serious problem worldwide and offers the bleakest outlook and prognosis. The number of reports of isolation of multiresistant strains is increasing, including antibiotics of the latest generation or exclusive intrahospital use. In this sense, isolates of strains resistant to practically all members of the quinolone family have been reported.

The implementation of appropriate practices in the use of antibiotics plays an important role in the fight against this serious global problem. The proper management of antibiotics must include limiting their use in the livestock, agricultural, and food industries; as well as the correct medical prescription, avoiding self-medication, and always seeking adherence to the full antibiotical treatment scheme.

**39**

Mexico

**Author details**

Sandra Georgina Solano-Gálvez1

Autónoma de México, Mexico

Diego Abelardo Álvarez-Hernández2

provided the original work is properly cited.

María José Ostos Prado2

, María Fernanda Valencia-Segrove2

and Rosalino Vázquez-López2

,

, Ana Berenice López Boucieguez<sup>2</sup>

The knowledge of the molecular mechanisms associated with resistance to quinolones and other antibiotics offers us great possibilities for molecular epidemiological monitoring of the emergence of new resistant strains, as well as their distribution. This knowledge offers the pharmaceutical industry the tools for the development of new drugs. It is important to consider that the development time of

new drugs is exceeded by the speed of appearance of new resistant strains.

1 Departamento de Microbiología, Facultad de Medicina de la Universidad Nacional

2 Departamento de Microbiología, Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: rosalino.vazquez@anahuac.mx

,

\*

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

*Antimicrobial Resistance - A One Health Perspective*

of various genotoxic chemicals [115].

into sul1-type integrons.

OqxAB pumps.

**7. Concluding remarks**

the quinolone family have been reported.

OqxAB [121].

fluoroquinines and nalidixic acid. This resistance phenomenon could be induced in a variety of bacteria deficient in outer-membrane porins. They also described that this plasmid promoted the acceleration of resistance development and its propagation. The gene responsible for this resistance was called *qnr*, later it became *qnrA* [113, 114]. In 2002, Tran and Jacoby, working with the qnr plasmid, managed to identify an integron-like environment upstream from qacEΔ1 and sulI. The product obtained from this gene was a 218-aa protein called QnrA. This protein belonging to the pentapeptide repeat family shared sequence homology with the immunity protein McbG. Previous studies suggested that McbG protects DNA gyrase from the action

Based on the mechanism of action of quinolones (the inhibition of topoisomerases I and IV) and the similarity of QnrA to McbG, Tran and Jacoby determined the ability of QnrA to induce resistance against quinolones by topoisomerase protection [115]. In 2005, two independent teams managed to determine the same activity as

Subsequent studies of the qnrA plasmid found that this plasmid was able to promote greater resistance than expected and that is how, in 2006, Ari Robicsek et al. discovered another mechanism of action of resistance to quinolones mediated by the enzymatic action of aminoglycoside acetyltransferase, AAC(6′)-Ib-cr. They also reported that the quinolone resistance mechanism was determined by reduction of the activity of ciprofloxacin by N-acetylation at the amino nitrogen on its piperazinyl substituent [118]. In 2007, three groups of researchers separately demonstrated another resistance

QnrA for two other proteins identified as QnrB [116] and QnrS [117].

mechanism encoded by plasmids. These works, in correlation with Martinez's works, involve quinolone efflux pumps mediated by plasmids QepA [119, 120] and

1.The plasmid genes *qnrA*, *qnrB*, *qnrC*, *qnrD*, *qnrS,* and *qnrVC* encode proteins from the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The *qnr* genes are generally associated with mobilizing or transposable elements in plasmids and are often incorporated

2.The second mechanism mediated by plasmids involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common

Bacterial resistance to antibiotics is a serious problem worldwide and offers the bleakest outlook and prognosis. The number of reports of isolation of multiresistant strains is increasing, including antibiotics of the latest generation or exclusive intrahospital use. In this sense, isolates of strains resistant to practically all members of

The implementation of appropriate practices in the use of antibiotics plays an important role in the fight against this serious global problem. The proper management of antibiotics must include limiting their use in the livestock, agricultural, and food industries; as well as the correct medical prescription, avoiding self-medication, and always seeking adherence to the full antibiotical treatment scheme.

In summary, there are three mechanisms for PMQR:

aminoglycoside acetyltransferase AAC(6′)-Ib-cr.

3.Improved outflow produced by plasmid genes for QepAB and

**38**

The knowledge of the molecular mechanisms associated with resistance to quinolones and other antibiotics offers us great possibilities for molecular epidemiological monitoring of the emergence of new resistant strains, as well as their distribution. This knowledge offers the pharmaceutical industry the tools for the development of new drugs. It is important to consider that the development time of new drugs is exceeded by the speed of appearance of new resistant strains.
