Disease relevance of gyrA

• With E. coli, a gyrA, but not a parC, mutation raised the MIC of both compounds [1].
• Selection of a gyrA Mutation and Treatment Failure with Gatifloxacin in a Patient with Streptococcus pneumoniae with a Preexisting parC Mutation [2].
• Resistance to multiple fluoroquinolones in a clinical isolate of Streptococcus pyogenes: identification of gyrA and parC and specification of point mutations associated with resistance [3].
• In vivo activity of gemifloxacin, moxifloxacin and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point [4].
• Double mutants in the parC and gyrA genes lead to fluoroquinolone resistance that has been found to cause bacteriological failure of the fluoroquinolones, particularly levofloxacin and ciprofloxacin, in the management of pneumonia and exacerbations of chronic bronchitis [5].

High impact information on gyrA

• Fluoroquinolone resistance in Streptococcus pneumoniae is primarily mediated by point mutations in the quinolone resistance-determining regions of gyrA and parC [6].
• Naturally occurring parC, parE, and gyrA loci containing mutations in the quinolone-resistance-determining regions were introduced by transformation into S. pneumoniae strain R6 individually and in combinations [7].
• PD models simulating fAUC/MICs of 51 and </=60, 34 and 37, </=82 and </=86, and </=24 for gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin, respectively, against each isolate were associated with first-step parC (S52G, S79Y, and N91D) and second-step gyrA (S81Y and S114G) mutations [8].
• First, ciprofloxacin-resistant parC mutants of strain 7785 remained susceptible to dimers 1 to 3, whereas a gyrA mutation conferred a four- to eightfold increase in the dimer MIC but had little effect on ciprofloxacin activity [9].
• Therapeutic moxifloxacin concentrations against the gyrA mutant KD2139 resulted in outgrowth of a mutant with a ParC substitution (S79Y) but caused no emergence of mutants of the other three isolates [10].

Chemical compound and disease context of gyrA

• The parC mutations were able to transform Streptococcus pneumoniae to ciprofloxacin resistance, while the gyrA mutations transformed S. pneumoniae only when mutations in parC were present [11].
• Sparfloxacin resistance in clinical isolates of Streptococcus pneumoniae: involvement of multiple mutations in gyrA and parC genes [12].
• Relationship between mutations in parC and gyrA of clinical isolates of Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin [13].

Biological context of gyrA

• A sequence-directed DNA curvature was identified in the promoter region of gyrA [14].
• Gene amplification and sequencing analysis of gyrA and parC revealed nucleotide changes leading to amino acid substitutions in both GyrA and ParC of all four fluoroquinolone-resistant isolates [12].
• The rate at which second-step mutants emerged was 1.3 x 10(-8) for parC Serine 79 Tyrosine and 7.2 x 10(-9) for gyrA Serine 81 Phenylalanine, 12 and 450 times higher, respectively, than for first-step rates, suggesting that mutation in either gene readies the genome for further mutation [15].
• Restriction fragment length polymorphism analysis following HinfI digestion was used with DNA sequencing to identify mutations in the quinolone resistance-determining regions (QRDRs) of the parC and gyrA genes [13].

Associations of gyrA with chemical compounds

• With S. aureus, the dimer selected spontaneous resistant gyrA mutants, whereas ciprofloxacin selected a parC mutant [1].
• The isolate obtained before therapy showed a preexisting parC mutation of aspartic acid-83 to asparagine (Asp83-->Asn), and the isolate obtained during therapy showed an acquired gyrA mutation from serine-81 to phenylalanine (Ser81-->Phe) and a second parC mutation from lysine-137 to Asn (Lys137-->Asn) [2].
• (ii) Gemifloxacin selected first-step gyrA mutants of S. pneumoniae 7785 (gemifloxacin MICs, 0.25 microgram/ml) encoding Ser-81 to Phe or Tyr, or Glu-85 to Lys mutations [16].
• The gyrA mutants were cross-resistant to gatifloxacin and sparfloxacin but were not resistant to the other fluoroquinolones tested [17].
• Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA [18].

Other interactions of gyrA

• Mutations in gyrB were important for resistance to gatifloxacin but not moxifloxacin, and mutation of gyrA was associated with resistance to moxifloxacin but not gatifloxacin, suggesting differences in the drug-target interactions of the two 8-methoxyquinolones [19].

Analytical, diagnostic and therapeutic context of gyrA

• For the isolates in this prevalence study, only parC (Ser-79-->Tyr) and gyrA (Ser-81-->Phe or Tyr) mutations, especially in combination, were found to contribute significantly to resistance [20].
• Mutant strains selected on gemifloxacin had only a modest increase in minimum inhibitory concentration; thus, second-round mutants were competed with a first-round gyrA Serine 81 to Tyrosine or the susceptible isogenic parent [21].
• Mutations in the quinolone resistance-determining region (QRDR) were characterized by PCR and sequencing of parC, parE, and gyrA [22].
• The genetic relatedness of isolates with parC and/or gyrA mutations from 2001-2002 (n=55) and from 3 US surveillance studies conducted during 1994-2000 (n=56) was determined by pulsed-field gel electrophoresis (PFGE) [23].

References