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Chapter 23 : Inhibitors of DNA Gyrase and Topoisomerase IV

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Inhibitors of DNA Gyrase and Topoisomerase IV, Page 1 of 2

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Abstract:

DNA gyrase and topoisomerase IV cleave double stranded DNA in both strands and then transport another segment of double-stranded DNA through the cleaved DNA segment before religating the DNA. Topoisomerases are divided into two classes, type I and type II. Type I topoisomerases, represented by Escherichia coli topoisomerases I and III, break single strands of duplex DNA, pass another single DNA strand through the break, and then reseal the break. In contrast, type II topoisomerases, represented by E. coli DNA gyrase and topoisomerase IV, break both strands of duplex DNA, pass other DNA duplex strands through the break, and reseal both breaks. Bacterial resistance to quinolones may result from chromosomal mutations coding for modifications in target subunits of bacterial topoisomerases II and IV or by active efflux via efflux pumps and alterations in the expression of outer membrane proteins, most importantly OmpF. The quinolones most strongly affected by a single mutation are those for which the mutations occur in their preferred target, for example in gyrase for sparfloxacin, grepafloxacin, gatifloxacin, gemifloxacin, clinafloxacin, and moxifloxacin and in topoisomerase IV for ciprofloxacin, norfloxacin, levofloxacin, and trovafloxacin. Resistance mutations in GyrB generally occur less often than those in GyrA and have been found in E. coli, Salmonella enterica serovar Typhimurium, Mycobacterium tuberculosis, Staphylococcus aureus, and Streptococcus pneumoniae. Quinolones must traverse the cell wall and cytoplasmic membrane of gram-positive bacteria and, additionally, the outer membrane of gram-negative bacteria to reach the DNA gyrase and topoisomerase IV in the cytoplasm.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Figures

Image of Figure 23.1
Figure 23.1

Chemical structures of the first-generation quinolones (structure 1), nalidixic acid (structure 2), cinoxacin (structure 3), and pipemidic acid (structure 4).

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.2
Figure 23.2

Chemical structures of second-generation quinolones.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.3
Figure 23.3

Chemical structures of thirdgeneration quinolones.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.4
Figure 23.4

A typical phone cord is coiled like a DNA helix, and the coiled cord can itself coil into a supercoil. Reprinted from D. L. Nelson and M. M. Cox, Lehninger Principles of Biochemistry, 3rd ed. (Worth Publishers, New York, N.Y., 2000), with permission from the publisher.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.5
Figure 23.5

Mechanism of the E. coli topoisomerase I reaction. This enzyme is not essential and is not inhibited by quinolones.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.6
Figure 23.6

Cooperative quinolone–DNA-binding model for DNA gyrase inhibition proposed by Shen et al. (1989). See the text for details. Reprinted from I. Morrissey, K. Hoshino, K. Sato, A. Yoshida, I. Hayakawa, M. G. Bures, and L. L. Shen, Antimicrob. Agents Chemother.40:1775–1784, 1996, with permission from the American Society for Microbiology.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.7
Figure 23.7

The model represented in Fig. 23.6 is further depicted by a brickstacking schematic presentation, with the symbols explained in the lower panel. Reprinted from I. Morrissey, K. Hoshino, K. Sato, A. Yoshida, I. Hayakawa, M. G. Bures, and L. L. Shen, Antimicrob. Agents Chemother. 40:1775–1784, 1996, with permission from the American Society for Microbiology.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Image of Figure 23.8
Figure 23.8

Functional domains of quinolone antibacterial agents.

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
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Tables

Generic image for table
Table 23.1

Mutations of E. coli in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV associated with quinolone resistance a

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
Generic image for table
Table 23.2

Mutations of E. coli in the GyrB subunit of DNA gyrase and the ParE subunit of topoisomerase IV associated with quinolone resistance a

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23
Generic image for table
Table 23.3

Generic and common trade names of quinolones, the preparations available, and manufacturers in the United States

Citation: Mascaretti O. 2003. Inhibitors of DNA Gyrase and Topoisomerase IV, p 295-309. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch23

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