Disease relevance of parC

• OBJECTIVES: The increasingly recognized prevalence of first-step parC mutants in Streptococcus pneumoniae and the development of de novo resistance while on fluoroquinolone therapy are of concern [1].
• With E. coli, a gyrA, but not a parC, mutation raised the MIC of both compounds [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].
• The ant-like gene was absent from typical S. pneumoniae strains, whereas it was present in the intergenic parE-parC regions of the viridans group streptococci (Streptococcus mitis and Streptococcus oralis) [4].
• In vitro exchange of fluoroquinolone resistance determinants between Streptococcus pneumoniae and viridans streptococci and genomic organization of the parE-parC region in S. mitis [5].

High impact information on parC

• Fluoroquinolone resistance in Streptococcus pneumoniae is primarily mediated by point mutations in the quinolone resistance-determining regions of gyrA and parC [6].
• Also evident were examples of interspecific transfer, with two isolates possessing a parE-parC gene region arising from viridans group streptococci [7].
• Gemifloxacin preferentially selected for parC mutants both in vitro and in vivo [8].
• Of the resistant isolates, 90.5% were M/emm type 6, and all sequenced M/emm type 6 isolates contained a serine-to-alanine substitution at position 79 in parC [9].
• 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 [10].

Chemical compound and disease context of parC

• Evaluation of bacterial kill when modelling the bronchopulmonary pharmacokinetic profile of moxifloxacin and levofloxacin against parC-containing isolates of Streptococcus pneumoniae [1].
• Selection of a gyrA Mutation and Treatment Failure with Gatifloxacin in a Patient with Streptococcus pneumoniae with a Preexisting parC Mutation [11].
• Mutants of wild-type Streptococcus pneumoniae IID553 with mutations in parC were obtained by selection with trovafloxacin, levofloxacin, norfloxacin, and ciprofloxacin [12].
• Sparfloxacin resistance in clinical isolates of Streptococcus pneumoniae: involvement of multiple mutations in gyrA and parC genes [13].
• Relationship between mutations in parC and gyrA of clinical isolates of Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin [14].

Biological context of parC

• The majority of mutations (67.3% of the mutations in 49 isolates with mutations) were amino acid substitutions in the parC locus only [15].
• Fourth, the GyrA S81F and ParC S79F enzymes were resistant to dimers, confirming that the resistance phenotype is largely silent in parC mutants [10].
• 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 [13].
• The nucleotide sequence of the full-length parC, parE, and gyrA genes of one of these isolates revealed a mosaic structure compatible with an interspecific recombination origin [4].
• Mutants were detected in treated animals infected with strains harbouring parC mutations (Cip8 and Cip10) and when the AUC/MIC ratio was between 13 and 31 [16].

Associations of parC with chemical compounds

• 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 [17].
• RESULTS: The dimer was lethal, in some cases exhibiting more activity than ciprofloxacin (particularly with wild-type cells and a parC mutant of S. aureus) [2].
• Previous work by our group demonstrated the ability of moxifloxacin, but not levofloxacin, to eradicate parC mutants [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) [11].
• Second-step mutants (gemifloxacin MICs, 1 microgram/ml) exhibited an alteration in parC resulting in changes of ParC hot spot Ser-79 to Phe or Tyr [18].

Other interactions of parC

• Asian Russian isolates had mutations in parC and gyrA, and alterations in parE were more common [19].
• Analysis of 71 ciprofloxacin-resistant (MIC > or = 4 microg/ml) Streptococcus pneumoniae clinical isolates revealed only 1 for which the quinolone resistance-determining regions of the parC, parE, and gyrB genes were genetically related to those of viridans group streptococci [20].

Analytical, diagnostic and therapeutic context of parC

• RESULTS: The isolate without a parC mutation displayed a 4 log reduction in cfu after treatment with levofloxacin 500 mg and did not select for resistance [1].
• A real-time PCR assay with locked nucleic acid probes was developed to screen mutations at codons 79 and 83 of the Streptococcus pneumoniae parC gene [21].
• 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 [22].
• The minimum inhibitory concentration (MIC) of ciprofloxacin for all isolates from the first 9 patients was 4 microg/mL, in association with a parC mutation [23].
• 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) [24].

References