Fluoroquinolone Resistance

Jordi Vila

doi:10.1128/9781555817572.ch4

Chapter 4 : Fluoroquinolone Resistance

Author: Jordi Vila¹

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Affiliations: 1: Department of Microbiology, Hospital Clinic, University of Barcelona, School of Medicine, Villarroel, 170, 08036 Barcelona, Spain

Content Type: Monograph

Publication Year: 2005

Category: Bacterial Pathogenesis

Book DOI: 10.1128/9781555817572

Chapter DOI: 10.1128/9781555817572.ch4

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Abstract:

Fluoroquinolones are an important class of widespectrum antibacterial agents. The DNA gyrase is known to play an important role in both the transcription and replication of DNA. Topoisomerase IV has also been found to be a protein target for quinolones. The major role of this enzyme seems to be in decatenating daughter replicons following DNA replication. The chromosomal mutations can be distributed into two groups: (i) mutations in topoisomerases genes (gyrA, gyrB, parC, and parE), and (ii) mutations causing reduced drug accumulation, either by a decreased uptake or by increased efflux. The high level of fluoroquinolone resistance observed in some countries is probably due to two factors. First, Campylobacter jejuni lacks topoisomerase IV; therefore a mutation in the gyrA gene is sufficient to increase the MIC of ciprofloxacin and levofloxacin above 32 mg/liter, whereas two mutations are necessary in the gyrA gene to generate a high level (32 mg/liter) of resistance to moxifloxacin. Second, the constitutive expression of the CmeABC pump contributes to the intrinsic resistance. NorA is one of the efflux systems related to fluoroquinolone resistance, and it seems that the increase in the level of resistance provided by NorA is due to the overexpression of the gene associated with a mutation in the promoter region. The molecular bases of fluoroquinolone resistance are similar in all microorganisms mainly due to mutations in the gyrA and parC genes, encoding the A subunits of the DNA gyrase and topoisomerase IV, the protein targets for quinolones.

Citation: Vila J. 2005. Fluoroquinolone Resistance, p 41-52. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch4

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Fluoroquinolone Resistance

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Figure 1.

Chemical structure of the main commercialized quinolones.

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Figure 1.

Chemical structure of the main commercialized quinolones.

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Figure 2.

Process of DNA replication and DNA transcription involving DNA gyrase and topoisomerase IV.

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Figure 2.

Process of DNA replication and DNA transcription involving DNA gyrase and topoisomerase IV.

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Figure 3.

Functional domains of the quinolone molecule according to Palumbo’s and Shen’s models.

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Figure 3.

Functional domains of the quinolone molecule according to Palumbo’s and Shen’s models.

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Figure 4.

(A) Distance between Ser-83 and Asp-87 of the GyrA protein. (B) Distance between substituents at positions 1 and 7 of the quinolone molecule.

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Figure 4.

(A) Distance between Ser-83 and Asp-87 of the GyrA protein. (B) Distance between substituents at positions 1 and 7 of the quinolone molecule.

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Tables

Fluoroquinolone Resistance

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Table 1

Classification of main commercialized quinolones

a Levofloxacin has been included in the third generation because it is more active than ofloxacin against gram-positive cocci and also because the serum peak allows a good therapeutic index against these microorganisms.

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Table 1

Classification of main commercialized quinolones

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Table 2

Mechanisms of resistance to fluoroquinolones in different microorganisms

a These are the most frequently found substitutions.

b The main efflux pumps for each microorganism are mentioned but are not related to the MIC in the table.

c Can be extrapolated to the remaining Enterobactertaceae.

d This microorganism does not have topoisomerase IV.

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Table 2

Mechanisms of resistance to fluoroquinolones in different microorganisms

a These are the most frequently found substitutions.

b The main efflux pumps for each microorganism are mentioned but are not related to the MIC in the table.

c Can be extrapolated to the remaining Enterobactertaceae.

d This microorganism does not have topoisomerase IV.

/content/10.1128/9781555817572.chap4.tab4-3

Table 3

Factors favoring emergence of quinolone resistance Factors dependent on the quinolone

a These factors generate a transitory resistance.

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Table 3

Factors favoring emergence of quinolone resistance Factors dependent on the quinolone

a These factors generate a transitory resistance.