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Chapter 23 : The Molecular Genetics of Fluoroquinolone Resistance in

Authors: Claudine Mayer1, Howard Takiff4
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Affiliations: 1: Unité de Microbiologie Structurale, Institut Pasteur; 2: UMR 3528 du CNRS; 3: Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, 75015, Paris, France; 4: Laboratorio de Genética Molecular, CMBC, IVIC, Caracas, Venezuela
Content Type: Monograph
Publication Year: 2014

Category: Microbial Genetics and Molecular Biology

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Abstract:

The fluoroquinolones (FQs) are among the most widely prescribed antibiotics globally and until very recently were the only new antibiotics accepted for use against tuberculosis (TB) in the past 40 years. They are an important component of drug regimens for curing strains resistant to other antibiotics, especially multidrug-resistant TB (MDR-TB)—strains resistant to at least isoniazid and rifampin ( ). They are also being proposed as first-line agents to reduce the duration of treatment for pan-susceptible strains, particularly when given in new combinations with other recently developed drugs ( ). A major problem with the FQs is the development of resistant strains. MDR strains that have developed resistance to the FQs and also to any of the injectable drugs are termed extensively drug-resistant (XDR-TB)—strains that are extremely difficult to treat ( ), with studies showing from 65% ( ) to less than 50% having favorable outcomes ( ). For the best chance of curing XDR-TB, resistance to FQs should be identified promptly so that alternative or additional antibiotics can be prescribed. So while there is intellectual interest in investigating the mechanisms and mutations through which develops FQ resistance, and the hope that this information will eventually lead to the design of more effective FQs or quinolone derivatives that are less susceptible to these resistance mechanisms, there is also an urgent need to define the mutations conferring resistance so they can be incorporated into rapid molecular tests to identify FQ-resistant strains.

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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The Molecular Genetics of Fluoroquinolone Resistance in Mycobacterium tuberculosis
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Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 1
Chemical structures of FQs.
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Figure 1

Chemical structures of FQs.

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 2
Schematic representation of the sequence and domain organization of type IIA topoisomerases formed by the association of two subunits, A and B. Bacterial type IIA topoisomerases are AB heterotetramers. The names of the four conserved domains are indicated. ( Proposed atomic and schematic model of the type IIA topoisomerase architecture. The three gates are indicated.
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Figure 2

Schematic representation of the sequence and domain organization of type IIA topoisomerases formed by the association of two subunits, A and B. Bacterial type IIA topoisomerases are AB heterotetramers. The names of the four conserved domains are indicated. ( Proposed atomic and schematic model of the type IIA topoisomerase architecture. The three gates are indicated.

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 3
Structure of the DNA gyrase catalytic core in complex with DNA and moxifloxacin in ribbon representation. Side view and top view of the molecular surface of the catalytic core. The Toprim domain is represented in red, the BRD in blue, the 35-base-pair DNA oligonucleotide in orange, and the moxifloxacin in green. Localization of the QRDR is indicated in pink and light blue (residues 500 to 538 for QRDR-B and 74 to 108 for QRDR-A). Close view of the structure of the intercalated moxifloxacin (magenta) in the broken DNA double helix (green). The catalytic tyrosine (Y129 in the DNA gyrase sequence) is shown in green outside the DNA helix. Close view of both moxifloxacin molecules in the broken DNA showing the 4 base pairs in between the two bound fluoroquinolones. Both catalytic tyrosines of each monomer are shown in green in the DNA major groove.
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Figure 3

Structure of the DNA gyrase catalytic core in complex with DNA and moxifloxacin in ribbon representation. Side view and top view of the molecular surface of the catalytic core. The Toprim domain is represented in red, the BRD in blue, the 35-base-pair DNA oligonucleotide in orange, and the moxifloxacin in green. Localization of the QRDR is indicated in pink and light blue (residues 500 to 538 for QRDR-B and 74 to 108 for QRDR-A). Close view of the structure of the intercalated moxifloxacin (magenta) in the broken DNA double helix (green). The catalytic tyrosine (Y129 in the DNA gyrase sequence) is shown in green outside the DNA helix. Close view of both moxifloxacin molecules in the broken DNA showing the 4 base pairs in between the two bound fluoroquinolones. Both catalytic tyrosines of each monomer are shown in green in the DNA major groove.

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 4
The schematic diagram in the center shows the arrangement of the and genes, encoding the GyrA and GyrB subunits of the DNA gyrase. Also shown are the locations of the TOPRIM region of GyrB, the BRD of GyrA, and the sites of the QRDRs of both subunits, QRDR-B or QRDR-A. Above the diagram is an alignment of the region of GyrB containing QRDR-B, illustrating that this region is highly conserved in the B subunits of the gyrases and the B subunits of the topoisomerase IV enzymes (ParE), as illustrated by the Gram-positive and the Gram-negative Below the diagram is the alignment of segments including the QRDR-A for the A subunits of the gyrase and topoisomerase IV from the same bacteria. The underlined letters in bold indicate amino acids where mutations confer FQ resistance. The blue Y in the GyrA alignment indicates the tyrosine that is covalently bound to the cleaved G segment DNA (see text). On the top and bottom of the figure are the nucleotide and amino acid sequences of the QRDR-A and QRDR-B regions, with the amino acid substitutions shown to confer FQ resistance. Amino acid 95 of the QRDR-A is polymorphic and can be either serine or threonine depending upon the phylogeny of the strain, but has not been implicated in FQ resistance ( ). Below the sequence of the QRDR-B are the amino acid numbers in both the old and new numbering systems.
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Figure 4

The schematic diagram in the center shows the arrangement of the and genes, encoding the GyrA and GyrB subunits of the DNA gyrase. Also shown are the locations of the TOPRIM region of GyrB, the BRD of GyrA, and the sites of the QRDRs of both subunits, QRDR-B or QRDR-A. Above the diagram is an alignment of the region of GyrB containing QRDR-B, illustrating that this region is highly conserved in the B subunits of the gyrases and the B subunits of the topoisomerase IV enzymes (ParE), as illustrated by the Gram-positive and the Gram-negative Below the diagram is the alignment of segments including the QRDR-A for the A subunits of the gyrase and topoisomerase IV from the same bacteria. The underlined letters in bold indicate amino acids where mutations confer FQ resistance. The blue Y in the GyrA alignment indicates the tyrosine that is covalently bound to the cleaved G segment DNA (see text). On the top and bottom of the figure are the nucleotide and amino acid sequences of the QRDR-A and QRDR-B regions, with the amino acid substitutions shown to confer FQ resistance. Amino acid 95 of the QRDR-A is polymorphic and can be either serine or threonine depending upon the phylogeny of the strain, but has not been implicated in FQ resistance ( ). Below the sequence of the QRDR-B are the amino acid numbers in both the old and new numbering systems.

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 5
Close view of the quinolone-binding pocket. The DNA-protein complex is represented in transparent molecular surface and moxifloxacin, in sticks (color code is the same as in Fig. 3 ). The residues of the QRDR-B (Toprim) belonging to the QBP are indicated in pink, purple, and yellow. Residue A90 of the QRDR-B is represented in light green in the background of the pocket. Effect of the substitution of A90 (QRDR-A) on the geometry of the quinolone-binding pocket. (Left) Quinolone-binding pocket of the wild-type DNA gyrase. The A90 is colored in yellow. (Middle) Substitution of A90 to serine (S90 is represented in green). (Right) Substitution of A90 to valine (V90 is represented in magenta).
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Figure 5

Close view of the quinolone-binding pocket. The DNA-protein complex is represented in transparent molecular surface and moxifloxacin, in sticks (color code is the same as in Fig. 3 ). The residues of the QRDR-B (Toprim) belonging to the QBP are indicated in pink, purple, and yellow. Residue A90 of the QRDR-B is represented in light green in the background of the pocket. Effect of the substitution of A90 (QRDR-A) on the geometry of the quinolone-binding pocket. (Left) Quinolone-binding pocket of the wild-type DNA gyrase. The A90 is colored in yellow. (Middle) Substitution of A90 to serine (S90 is represented in green). (Right) Substitution of A90 to valine (V90 is represented in magenta).

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 6
The sequence of the QRDR-A region from the initial patient isolate shows a wild-type GAC encoding aspartic acid at codon 94. In an isolate taken after 7 months of FQ therapy, the QRDR-A sequence shows that two mutant bacilli populations were present, one with a GCC encoding an alanine at codon 94 and one with GGC encoding glycine at codon 94. By month 10 the bacteria containing the D94G substitution predominated, and the population with the D94A substitution was no longer detected by sequencing. Figure modified from reference .
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Figure 6

The sequence of the QRDR-A region from the initial patient isolate shows a wild-type GAC encoding aspartic acid at codon 94. In an isolate taken after 7 months of FQ therapy, the QRDR-A sequence shows that two mutant bacilli populations were present, one with a GCC encoding an alanine at codon 94 and one with GGC encoding glycine at codon 94. By month 10 the bacteria containing the D94G substitution predominated, and the population with the D94A substitution was no longer detected by sequencing. Figure modified from reference .

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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Figure 7
Side and top views of the MfpA dimer shown in Cα trace (PDB code 2BM5). Top and side views showing how MfpA mimics a 30-base pair B-form DNA. Model of the interaction between the DNA gyrase catalytic core (represented in blue molecular surface) and MfpA (represented in magenta cartoon).
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Image of Figure 7
Figure 7

Side and top views of the MfpA dimer shown in Cα trace (PDB code 2BM5). Top and side views showing how MfpA mimics a 30-base pair B-form DNA. Model of the interaction between the DNA gyrase catalytic core (represented in blue molecular surface) and MfpA (represented in magenta cartoon).

Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in , p 455-478. In Hatfull G, Jacobs W (ed), Molecular Genetics of Mycobacteria, Second Edition. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MGM2-0009-2013
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