Mechanism of Binding of Fluoroquinolones to the Quinolone Resistance-Determining Region of DNA Gyrase: Towards an Understanding of the Molecular Basis of Quinolone Resistance

ChemBioChem ◽  
2008 ◽  
Vol 9 (13) ◽  
pp. 2081-2086 ◽  
Author(s):  
Sergio Madurga ◽  
Javier Sánchez-Céspedes ◽  
Ignasi Belda ◽  
Jordi Vila ◽  
Ernest Giralt
Keyword(s):  
Molecular Basis ◽  
Dna Gyrase ◽  
Quinolone Resistance

scholarly journals Extending the Definition of the GyrB Quinolone Resistance-Determining Region in Mycobacterium tuberculosis DNA Gyrase for Assessing Fluoroquinolone Resistance in M. tuberculosis

2012 ◽  
Vol 56 (4) ◽  
pp. 1990-1996 ◽  
Author(s):  
Alix Pantel ◽  
Stéphanie Petrella ◽  
Nicolas Veziris ◽  
Florence Brossier ◽  
Sylvaine Bastian ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Hot Spot ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Fluoroquinolone Resistance ◽  
Wild Type ◽  
Content Type ◽  
Highly Active ◽  
Definition Of

ABSTRACTFluoroquinolone (FQ) resistance is emerging inMycobacterium tuberculosis. The main mechanism of FQ resistance is amino acid substitution within the quinolone resistance-determining region (QRDR) of the GyrA subunit of DNA gyrase, the sole FQ target inM. tuberculosis. However, substitutions in GyrB whose implication in FQ resistance is unknown are increasingly being reported. The present study clarified the role of four GyrB substitutions identified inM. tuberculosisclinical strains, two located in the QRDR (D500A and N538T) and two outside the QRDR (T539P and E540V), in FQ resistance. We measured FQ MICs and also DNA gyrase inhibition by FQs in order to unequivocally clarify the role of these mutations in FQ resistance. Wild-type GyrA, wild-type GyrB, and mutant GyrB subunits produced from engineeredgyrBalleles by mutagenesis were overexpressed inEscherichia coli, purified to homogeneity, and used to reconstitute highly active gyrase complexes. MICs and DNA gyrase inhibition were determined for moxifloxacin, gatifloxacin, ofloxacin, levofloxacin, and enoxacin. All these substitutions are clearly implicated in FQ resistance, underlining the presence of a hot spot region housing most of the GyrB substitutions implicated in FQ resistance (residues NTE, 538 to 540). These findings help us to refine the definition of GyrB QRDR, which is extended to positions 500 to 540.

scholarly journals Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5662
Author(s):  
Natassja G. Bush ◽  
Isabel Diez-Santos ◽  
Lauren R. Abbott ◽  
Anthony Maxwell
Keyword(s):  
Cell Death ◽  
Antibiotic Resistance ◽  
Dna Gyrase ◽  
Mechanisms Of Action ◽  
Quinolone Resistance ◽  
Topoisomerase Iv ◽  
Bacterial Enzymes ◽  
Dna Topoisomerase ◽  
Quinolone Antibiotics ◽  
Dna Complex

Fluoroquinolones (FQs) are arguably among the most successful antibiotics of recent times. They have enjoyed over 30 years of clinical usage and become essential tools in the armoury of clinical treatments. FQs target the bacterial enzymes DNA gyrase and DNA topoisomerase IV, where they stabilise a covalent enzyme-DNA complex in which the DNA is cleaved in both strands. This leads to cell death and turns out to be a very effective way of killing bacteria. However, resistance to FQs is increasingly problematic, and alternative compounds are urgently needed. Here, we review the mechanisms of action of FQs and discuss the potential pathways leading to cell death. We also discuss quinolone resistance and how quinolone treatment can lead to resistance to non-quinolone antibiotics.

scholarly journals Mutation in the DNA Gyrase A Gene ofEscherichia coli That Expands the Quinolone Resistance-Determining Region

2001 ◽  
Vol 45 (8) ◽  
pp. 2378-2380 ◽  
Author(s):  
S. Marvin Friedman ◽  
Tao Lu ◽  
Karl Drlica
Keyword(s):  
Escherichia Coli ◽  
Amino Acids ◽  
Amino Acid ◽  
Dna Gyrase ◽  
Ofescherichia Coli ◽  
Quinolone Resistance ◽  
Gyrase A

ABSTRACT In three Escherichia coli mutants, a change (Ala-51 to Val) in the gyrase A protein outside the standard quinolone resistance-determining region (QRDR) lowered the level of quinolone susceptibility more than changes at amino acids 67, 82, 84, and 106 did. Revision of the QRDR to include amino acid 51 is indicated.

scholarly journals Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli.

1990 ◽  
Vol 34 (6) ◽  
pp. 1271-1272 ◽  
Author(s):  
H Yoshida ◽  
M Bogaki ◽  
M Nakamura ◽  
S Nakamura
Keyword(s):  
Escherichia Coli ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Gyra Gene

scholarly journals DNA Sequence Analysis of DNA Gyrase and DNA Topoisomerase IV Quinolone Resistance-Determining Regions of Salmonella enterica Serovar Typhi and Serovar Paratyphi A

2002 ◽  
Vol 46 (10) ◽  
pp. 3249-3252 ◽  
Author(s):  
Kenji Hirose ◽  
Ai Hashimoto ◽  
Kazumichi Tamura ◽  
Yoshiaki Kawamura ◽  
Takayuki Ezaki ◽  
...  
Keyword(s):  
Sequence Analysis ◽  
Dna Sequence ◽  
Salmonella Enterica ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Fluoroquinolone Resistance ◽  
Single Mutation ◽  
Topoisomerase Iv ◽  
Dna Topoisomerase ◽  
Salmonella Enterica Serovar Typhi

ABSTRACT The mutations that are responsible for fluoroquinolone resistance in the gyrA, gyrB, parC, and parE genes of Salmonella enterica serovar Typhi and serovar Paratyphi A were investigated. The sequences of the quinolone resistance-determining region of the gyrA gene in clinical isolates which showed decreased susceptibilities to fluoroquinolones had a single mutation at either the Ser-83 or the Asp-87 codon, and no mutations were found in the gyrB, parC, and parE genes.

Impact of mutations in DNA gyrase genes on quinolone resistance inCampylobacter jejuni

2016 ◽  
Vol 8 (10) ◽  
pp. 1071-1076 ◽  
Author(s):  
Ruchirada Changkwanyeun ◽  
Tomoyuki Yamaguchi ◽  
Siriporn Kongsoi ◽  
Kanjana Changkaew ◽  
Kazumasa Yokoyama ◽  
...  
Keyword(s):  
Dna Gyrase ◽  
Quinolone Resistance

scholarly journals Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus.

1996 ◽  
Vol 40 (5) ◽  
pp. 1157-1163 ◽  
Author(s):  
J Yamagishi ◽  
T Kojima ◽  
Y Oyamada ◽  
K Fujimoto ◽  
H Hattori ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Gene Dosage ◽  
Dna Gyrase ◽  
Quinolone Resistance ◽  
Wild Type Allele ◽  
Wild Type ◽  
Topoisomerase Iv ◽  
Dna Topoisomerase ◽  
Transformation Experiment ◽  
Dna Fragment

A 4.2-kb DNA fragment conferring quinolone resistance was cloned from a quinolone-resistant clinical isolate of Staphylococcus aureus and was shown to possess a part of the grlB gene and a mutated grlA gene. S-80-->F and E-84-->K mutations in the grlA gene product were responsible for the quinolone resistance. The mutated grlA genes responsible for quinolone resistance were dominant over the wild-type allele, irrespective of gene dosage in a transformation experiment with the grlA gene alone. However, dominance by mutated grlA genes depended on gene dosage when bacteria were transformed with the grlA and grlB genes in combination. Quinolone-resistant gyrA mutants were easily isolated from a strain, S. aureus RN4220, carrying a plasmid with the mutated grlA gene, though this was not the case for other S. aureus strains lacking the plasmid. The elimination of this plasmid from such quinolone-resistant gyrA mutants resulted in marked increases in quinolone susceptibility. These results suggest that both DNA gyrase and DNA topoisomerase IV may be targets of quinolones and that the quinolone susceptibility of organisms may be determined by which of these enzymes is most quinolone sensitive.

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