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Chapter 2 : Mechanisms of Quinolone Action

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Abstract:

This chapter introduces the quinolones with a brief consideration of DNA topoisomerases and quinolone target preference. Throughout the chapter attention is given to fluoroquinolone structure. Recently discovered examples include the relaxation of supercoils associated with infection of cultured macrophages by serovar Typhimurium and with hydrogen peroxide treatment of . The bacterial topoisomerases are divided into three groups: type I (topoisomerases I and III), type II (gyrase and topoisomerase IV), and specialized topoisomerases (enzymes that catalyze transposition or integration/excision of bacteriophage DNA from the bacterial chromosome). A function of topoisomerase I is the topological destabilization of transcription-mediated R loops. Another is likely to be control of global supercoiling, since a defect that raises supercoiling also suppresses a mutation, a defect that has a global effect on chromosome condensation. Quinolone binding to these mutant gyrase-DNA complexes induces a conformational change that can be detected in the GyrB subunit by limited proteolysis. The location of the quinolone-gyrase-DNA complexes on the bacterial chromosome is likely to influence the potential damage that quinolones can cause. The bacteriostatic effects of the quinolones are now understood at a level sufficient to allow structure-function interpretations. From a clinical perspective, there is a need to identify safe compounds that rapidly kill bacteria, especially resistant mutants. However, further refinement could become an academic exercise if ways are not developed to slow the emergence of fluoroquinolone-resistant pathogens.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Figure 1

Structures of commonly studied fluroquinolones.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Figure 2

Model of supercoiling and relaxation by DNA gyrase. (a) The 43-kDa and 47-kDa regions of GyrB, along with the 64-kDa region of GyrA are shown as a tetramer. The 33-kDa C-terminal domains of GyrA are omitted for clarity, as is the DNA wrap around gyrase. Supercoiling occurs when gyrase either binds a G segment of DNA (a) or assembles onto the G segment (b). The resulting complex (c) is a substrate for quinolone binding. The ternary complex (c) cleaves DNA to form a cleavage complex (d). ATP binds to the 43-kDa domains of GyrB, causing them to close and capture the T segment of DNA (e). The T segment is transported through the break in the G segment and into the bottom cavity of gyrase (f). The break in the G segment is religated (g), and the T segment is then released from the bottom cavity through the exit gate in the enzyme (h). The exit gate closes, resetting the enzyme for a new round of supercoiling. Between capture of the T segment and resetting of the enzyme, ATP is hydrolyzed and released. The figure was provided by Dr. J. G. Heddle (John Innes Centre, Norwich, United Kingdom). Reprinted from reference 83 by courtesy of Marcel Dekker, Inc.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Figure 3

Structure of DNA gyrase GyrA59 dimer. The figure shows a ribbon representation (generated in RasMol) of the GyrA59 fragment ( ), courtesy of J.G. Heddle (John Innes Centre). The upper panel shows the entire GyrA59 dimer while the lower panel is an enlargement of the boxed region in the upper panel. Amino acids that change to confer quinolone resistance are indicated in black and by the amino acid numbers. Amino acid 51 is in helix 2, amino acid 67 is in helix 3, and amino acids 83 and 87 are in helix 4. The figure was adapted from reference 61. Arrows in the upper panel indicate the location of changes that increase illegitimate recombination and spontaneous induction of lambda prophage as described in reference 7.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Figure 4

Proposed quinolone binding site. Orientation of fluoroquinolones and GyrA oc-helix-4. a-Helix-4, adapted from the crystal structure of the breakage-reunion domain of the GyrA protein of ( ), is drawn parallel to the long axis of the fluoroquinolone. For clarity, amino acid numbers represent positions in the GyrA protein. (The experiments were performed with position 81 in the figure corresponds to 89 in Arrows indicate positions of an ethyl group that changes the identity of the most resistant mutant (see text). The figure was adapted from reference 150.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Figure 5

Effect of GyrA variation on susceptibility to fluoroquinolones. MIC was determined for two structurally similar fluoroquinolones with the indicated fluoroquinolone-resistant mutants of . (The changes in the GyrA variants are indicated by standard amino acid abbreviations with the letter preceeding the number indicating the wild-type amino acid and the letter following the number representing the variant; the numbers used correspond to those shown in Fig. 4 and represent positions numbered according to the GyrA protein.) Panel A utilized fluoroquinolone PD161144, which has an ethyl group attached to the C-7 ring nitrogen as indicated by an arrow in Fig. 4 . Panel B utilized fluoroquinolone PD161148, which has its ethyl group attached to a C-7 ring carbon adjacent to the nitrogen indicated in Fig. 4 . The figure was adapted from data presented in reference 150.

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
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Tables

Generic image for table
Table 1

Inhibition of purified topoisomerase activity by fluoroquinolones

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2
Generic image for table
Table 2

Primary fluoroquinolone targets defined genetically in

Citation: Drlica K, Hooper D. 2003. Mechanisms of Quinolone Action, p 19-40. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch2

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