Disease relevance of gyrA

• OBJECTIVES: This study was aimed at characterizing the gyrA locus and determining its impact on fluoroquinolone susceptibility, DNA supercoiling degree and growth rate of Salmonella Typhimurium live vaccine strain vacT in comparison with its parent M415 [1].
• Life-threatening infantile diarrhea from fluoroquinolone-resistant Salmonella enterica typhimurium with mutations in both gyrA and parC [2].

High impact information on gyrA

• For nalidixic acid-resistant isolates, the ciprofloxacin MIC was eightfold higher than that for susceptible isolates, and the nalidixic acid-resistant isolates contained a single point mutation in the gyrA gene (at codons for Ser83 or Asp87) [3].
• Single gyrA mutations were also found in highly resistant in vitro-selected mutants (MIC of ciprofloxacin, 8 microg/ml), which indicates that mechanisms other than the unique modification of the intracellular targets could participate in fluoroquinolone resistance in Salmonella spp [4].
• An assay combining allele-specific PCR and restriction fragment length polymorphism was developed to rapidly screen mutations at codons 81, 83, and 87 of gyrA [4].
• An allele of gyrA prevents Salmonella enterica serovar Typhimurium from using succinate as a carbon source [5].
• The impact of gyrA mutations on the fluoroquinolone susceptibilities and relative DNA supercoiling degrees was investigated by a complementation assay using wild-type gyrA (gyrA+) and a reporter gene system, respectively [1].

Chemical compound and disease context of gyrA

• Here, we investigated the presence of mutations in the efflux regulatory genes of fluoroquinolone- and multidrug-resistant mutants of Salmonella enterica serovar Typhimurium (S. Typhimurium) selected in vitro with enrofloxacin that both carried a mutation in the target gene gyrA and overproduced the AcrAB efflux pump [6].

Biological context of gyrA

• Role of novel gyrA mutations in the suppression of the fluoroquinolone resistance genotype of vaccine strain Salmonella Typhimurium vacT (gyrA D87G) [1].
• Typhimurium representative single-step mutants showed reduced susceptibilities associated with point mutations in the QRDR of the gyrA gene or efflux pump system [7].
• Fifty-eight of the strains tested were indistinguishable by several different typing methods including antibiograms, pulsed-field gel gel electrophoresis, and plasmid profiling, although they could be further subdivided according to gyrA mutation [8].
• Fluoroquinolone treatment of experimental Salmonella enterica serovar Typhimurium DT104 infections in chickens selects for both gyrA mutations and changes in efflux pump gene expression [9].
• No mutations conferring an amino acid substitution in parC (the gene encoding the secondary target for quinolones) were revealed in the 48 isolates requiring 0.5-1 mg/L ciprofloxacin for inhibition, or the isolates for which no mutation in gyrA was revealed [10].

Associations of gyrA with chemical compounds

• Selection for novobiocin resistance allowed isolation of a mutation in the gyrA gene (allele gyrA659), a T467S substitution, which partially suppresses the supercoiling defect of gyrB651 [11].
• A mutant gyrA allele resulting in an A271E substitution in the DNA gyrase protein generated a strain unable to grow on the C(4)-dicarboxylates succinate, malate, and fumarate [5].
• In 2003, we identified five S. enterica serovar Typhimurium clinical isolates with high-level fluoroquinolone resistance (ciprofloxacin MIC, 16 microg/ml) with two point mutations in the gyrA gene (coding for Ser83-->Phe and Asp87-->Asn) and one point mutation in the parC gene (coding for Ser80-->Arg) [3].
• Nucleotide substitutions were identified in the gyrA gene of all except two isolates; all substitutions conferred a substitution at serine 83 or aspartate 87, as has previously been shown for isolates from humans [10].

Other interactions of gyrA

• This is the first example of a gyrA mutation that compensates for a gyrB defect [11].
• Moreover point mutations in the QRDR of the gyrA and parC genes were investigated by sequencing [7].
• The potency to protect pigs against colonization and against clinical salmonellosis was evaluated after oral immunization with a live gyrA-cpxA-rpoB Salmonella (S.) Typhimurium mutant (S. Tm. Nal2/Rif9/Rtt) [12].
• Thus, this study underlines the role of an acrR mutation, in addition to the mutation in gyrA, in the fluoroquinolone and multidrug resistance phenotype of S [6].

Analytical, diagnostic and therapeutic context of gyrA

• In view of the high MPC/MIC ratio, MAR strains with wild-type gyrA, although susceptible to ciprofloxacin (MICs 0.06-0.13 mg/L), may give rise to treatment failures [13].
• Sequence analysis of the quinolone resistance determining region (QRDR) of gyrA of 15 multiresistant strains conferring additional resistance to nalidixic acid and ciprofloxacin (R-type ACSSuSpTNxCp) identified two discrete base substitutions at codon Asp-87 [14].

References