Disease relevance of gyrA

• Association between early inhibition of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12 [1].
• RESULTS: The Salmonella Infantis isolate exhibited the Asp87-->Tyr87 mutation in gyrA, but no resistance-mediating mutations in the other target genes [2].
• Molecular cloning of the gyrA gene and characterization of its mutation in clinical isolates of quinolone-resistant Edwardsiella tarda [3].
• Degenerate primers for the amplification of gyrA were designed from consensus nucleotide sequences of gyrA from 9 different Gram-negative bacteria, including Escherichia coli [3].
• The amino acid sequence derived from the nucleotide sequence is about 50% homologous with that derived from the Bacillus subtilis gyrA gene sequence, with several regions showing greater than 90% homology [4].

High impact information on gyrA

• In the Deltafis strain, both topA and gyrA/B genes were found to be upregulated [5].
• The hisU1820 mutant of S. typhimurium exhibits many of the same phenotypes as hisW mutants [6].
• The hisW mutations of Salmonella typhimurium are highly pleiotropic mutations that elevate his operon expression, reduce ilv gene expression, alter stable RNA metabolism, and confer defective growth properties [6].
• The subunits can be identified as the products of two genes, determining resistance to coumermycin A1 and novobiocin (cou) and to nalidixic acid and oxolinic acid (nalA), respectively [7].
• Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme [8].

Chemical compound and disease context of gyrA

• Fusions of the Escherichia coli gyrA and gyrB control regions to the galactokinase gene are inducible by coumermycin treatment [9].
• Enoxacin inhibits growth of Escherichia coli K12 strains primarily by binding to the GyrA subunit of DNA gyrase (topoisomerase II); strains with gyrA, but not gyrB, mutations are less susceptible to the bactericidal effects of this agent [10].
• In the absence of the gyrA mutation, the parC (CipR) allele did not by itself confer resistance to ciprofloxacin, indicating that gyrase is the major quinolone target in E. coli [11].
• Treatment with EDTA decreased the ID50 of ciprofloxacin for P. aeruginosa PAO503 and its gyrA derivative by 5- and 2-fold, respectively, and decreased the ID50 for E. coli JB5R, a strain with a known decrease in OmpF, by 1.4-fold but did not decrease the ID50 for the normally susceptible E. coli J53 [12].
• gyrA and parC mutations have been identified inn Streptococcus pneumoniae mutants stepwise selected for resistance to sparfloxacin, an antipneumococcal fluoroquinolone [13].

Biological context of gyrA

• Fragments of gyrA and parC encompassing the quinolone resistance-determining region were amplified by PCR, and the DNA sequences of the fragments were determined [14].
• Introduction of a plasmid carrying both gyrA and gyrB genes into S. typhimurium 80190 restored the wildtype sensitivity [15].
• Enoxacin, even at subminimal inhibitory concentrations, induces the bacterial SOS system, even in partially resistant gyrA strains [10].
• The nucleotide sequence of gyrA was highly homologous to those of other bacterial species, in both the whole open-reading frame and the quinolone-resistance-determining region (QRDR) [3].
• The 2637-bp gyrA gene encodes a protein of 878 amino acids, preceded by a putative promoter, ribosome binding site and inverted repeated sequences for cruciform structures of DNA [3].

Anatomical context of gyrA

• A clinical isolate of Escherichia coli HM73 (MIC norfloxacin 2 mg/L) was isolated during norfloxacin therapy from an urinary tract infection in a patient who had been previously treated with pipemidic acid and infected by E. coli HM72 (norfloxacin 0.25), known to harbour a substitution Ser 83-->Leu in the gyrA gene [16].

Associations of gyrA with chemical compounds

• There were significant differences (P less than 0.001) between individual quinolones in the degree of DNA synthesis inhibition in nalidixic acid-resistant gyrA and nfxB(ompF) mutant strains [1].
• All isolates contained a mutation in gyrA of a serine at position 83 (Ser83) to an Leu, and 26 isolates also contained a mutation of Asp87 to one of four amino acids: Asn (n = 14), Tyr (n = 6), Gly (n = 5), or His (n = 1) [14].
• One, designated cfxA, conferred a 16-fold increase in drug resistance and mapped in a location consistent with a gyrA mutation; similar increases in resistance to ciprofloxacin were seen with gyrA mutations selected for resistance to other quinolones [17].
• The nucleotide sequence revealed that one of the gyrA mutants has a base change from G to A at position 641 (resulting in an amino acid change from Gly to Glu at position 214) of the gyrA gene [18].
• These results demonstrate that in clinical practice, gyrA mutations are the major mechanism of resistance to fluoroquinolones even in the strains of P. aeruginosa resistant to imipenem and lacking OprD, concomitant resistance to these drugs being the result of the addition of at least two independent mechanisms [19].

Regulatory relationships of gyrA

• We examined, in Escherichia coli, the influence of recA mutant alleles on the level of quinolone resistance promoted by mutations in the gyrA gene [20].

Other interactions of gyrA

• At higher osmolarity most compensatory mutations, as expected, are in the gyrA and gyrB genes [21].
• Mutation in parC appears to be a prerequisite before mutations in gyrA can influence resistance levels [22].
• In this paper we describe fusions of both the gyrA and gyrB 5' sequences to the E. coli galactokinase gene [9].
• We determined the nucleotide sequence of a 6-kb DNA region harboring the recF, orf192, gyrB, and gyrA genes from Mycobacterium smegmatis mc(2)155 [23].
• The basal and the polyamine-dependent expression of uvrA gene are not dependent on gyrA mutation [24].

Analytical, diagnostic and therapeutic context of gyrA

• Sequence analysis of the gyrA gene in all isolates identified only 1 nucleotide substitution at codon Serine-83 for Leucine-83 [25].
• The genotypic variation, based on the silent mutations in gyrA identified by the denaturing high-performance liquid chromatography pattern and DNA sequencing, was used to supplement typing data and provided evidence for both the spread of preexisting resistant strains and the selection of spontaneous resistant mutants in treated flocks [26].
• Molecular epidemiology and mutations at gyrA and parC genes of ciprofloxacin-resistant Escherichia coli isolates from a Taiwan medical center [27].
• Crystallization and preliminary X-ray crystallographic studies on the parD-encoded protein Kid from Escherichia coli plasmid R1 [28].

References