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The Molecular Genetics of Fluoroquinolone Resistance in

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  • Authors: Claudine Mayer1, Howard Takiff4
  • Editors: Graham F. Hatfull5, William R. Jacobs Jr.6
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    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; 5: University of Pittsburgh, Pittsburgh, PA; 6: Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY
  • Source: microbiolspec July 2014 vol. 2 no. 4 doi:10.1128/microbiolspec.MGM2-0009-2013
  • Received 16 April 2013 Accepted 06 August 2013 Published 11 July 2014
  • H. Takiff, htakiff@gmail.com
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  • Abstract:

    The fluoroquinolones (FQs) are synthetic antibiotics effectively used for curing patients with multidrug-resistant tuberculosis (TB). When a multidrug-resistant strain develops resistance to the FQs, as in extensively drug-resistant strains, obtaining a cure is much more difficult, and molecular methods can help by rapidly identifying resistance-causing mutations. The only mutations proven to confer FQ resistance in occur in the FQ target, the DNA gyrase, at critical amino acids from both the gyrase A and B subunits that form the FQ binding pocket. GyrA substitutions are much more common and generally confer higher levels of resistance than those in GyrB. Molecular techniques to detect resistance mutations have suboptimal sensitivity because gyrase mutations are not detected in a variable percentage of phenotypically resistant strains. The inability to find gyrase mutations may be explained by heteroresistance: bacilli with a resistance-conferring mutation are present only in a minority of the bacterial population (>1%) and are therefore detected by the proportion method, but not in a sufficient percentage to be reliably detected by molecular techniques. Alternative FQ resistance mechanisms in other bacteria—efflux pumps, pentapeptide proteins, or enzymes that inactivate the FQs—have not yet been demonstrated in FQ-resistant but may contribute to intrinsic levels of resistance to the FQs or induced tolerance leading to more frequent gyrase mutations. Moxifloxacin is currently the best anti-TB FQ and is being tested for use with other new drugs in shorter first-line regimens to cure drug-susceptible TB.

  • Citation: Mayer C, Takiff H. 2014. The Molecular Genetics of Fluoroquinolone Resistance in . Microbiol Spectrum 2(4):MGM2-0009-2013. doi:10.1128/microbiolspec.MGM2-0009-2013.

Key Concept Ranking

Outer Membrane Proteins
0.45742074
Type IIA Topoisomerase
0.45050526
Type II Topoisomerase
0.4344511
0.45742074

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/content/journal/microbiolspec/10.1128/microbiolspec.MGM2-0009-2013
2014-07-11
2017-11-21

Abstract:

The fluoroquinolones (FQs) are synthetic antibiotics effectively used for curing patients with multidrug-resistant tuberculosis (TB). When a multidrug-resistant strain develops resistance to the FQs, as in extensively drug-resistant strains, obtaining a cure is much more difficult, and molecular methods can help by rapidly identifying resistance-causing mutations. The only mutations proven to confer FQ resistance in occur in the FQ target, the DNA gyrase, at critical amino acids from both the gyrase A and B subunits that form the FQ binding pocket. GyrA substitutions are much more common and generally confer higher levels of resistance than those in GyrB. Molecular techniques to detect resistance mutations have suboptimal sensitivity because gyrase mutations are not detected in a variable percentage of phenotypically resistant strains. The inability to find gyrase mutations may be explained by heteroresistance: bacilli with a resistance-conferring mutation are present only in a minority of the bacterial population (>1%) and are therefore detected by the proportion method, but not in a sufficient percentage to be reliably detected by molecular techniques. Alternative FQ resistance mechanisms in other bacteria—efflux pumps, pentapeptide proteins, or enzymes that inactivate the FQs—have not yet been demonstrated in FQ-resistant but may contribute to intrinsic levels of resistance to the FQs or induced tolerance leading to more frequent gyrase mutations. Moxifloxacin is currently the best anti-TB FQ and is being tested for use with other new drugs in shorter first-line regimens to cure drug-susceptible TB.

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FIGURE 1

Chemical structures of FQs. doi:10.1128/microbiolspec.MGM2-0009-2013.f1

Source: microbiolspec July 2014 vol. 2 no. 4 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. doi:10.1128/microbiolspec.MGM2-0009-2013.f2

Source: microbiolspec July 2014 vol. 2 no. 4 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. doi:10.1128/microbiolspec.MGM2-0009-2013.f3

Source: microbiolspec July 2014 vol. 2 no. 4 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 ( 20 , 155 ). Below the sequence of the QRDR-B are the amino acid numbers in both the old and new numbering systems. doi:10.1128/microbiolspec.MGM2-0009-2013.f4

Source: microbiolspec July 2014 vol. 2 no. 4 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). doi:10.1128/microbiolspec.MGM2-0009-2013.f5

Source: microbiolspec July 2014 vol. 2 no. 4 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 78 . doi:10.1128/microbiolspec.MGM2-0009-2013.f6

Source: microbiolspec July 2014 vol. 2 no. 4 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). doi:10.1128/microbiolspec.MGM2-0009-2013.f7

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