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Gene Review

parC  -  DNA topoisomerase IV subunit A

Streptococcus pneumoniae R6

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Disease relevance of parC


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


Biological context of parC


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


  1. Evaluation of bacterial kill when modelling the bronchopulmonary pharmacokinetic profile of moxifloxacin and levofloxacin against parC-containing isolates of Streptococcus pneumoniae. Deryke, C.A., Du, X., Nicolau, D.P. J. Antimicrob. Chemother. (2006) [Pubmed]
  2. Bactericidal activity and target preference of a piperazinyl-cross-linked ciprofloxacin dimer with Staphylococcus aureus and Escherichia coli. Zhao, X., Quinn, B., Kerns, R., Drlica, K. J. Antimicrob. Chemother. (2006) [Pubmed]
  3. Resistance to multiple fluoroquinolones in a clinical isolate of Streptococcus pyogenes: identification of gyrA and parC and specification of point mutations associated with resistance. Yan, S.S., Fox, M.L., Holland, S.M., Stock, F., Gill, V.J., Fedorko, D.P. Antimicrob. Agents Chemother. (2000) [Pubmed]
  4. Viridans group streptococci are donors in horizontal transfer of topoisomerase IV genes to Streptococcus pneumoniae. Balsalobre, L., Ferrándiz, M.J., Liñares, J., Tubau, F., de la Campa, A.G. Antimicrob. Agents Chemother. (2003) [Pubmed]
  5. In vitro exchange of fluoroquinolone resistance determinants between Streptococcus pneumoniae and viridans streptococci and genomic organization of the parE-parC region in S. mitis. Janoir, C., Podglajen, I., Kitzis, M.D., Poyart, C., Gutmann, L. J. Infect. Dis. (1999) [Pubmed]
  6. Relative fitness of fluoroquinolone-resistant Streptococcus pneumoniae. Johnson, C.N., Briles, D.E., Benjamin, W.H., Hollingshead, S.K., Waites, K.B. Emerging Infect. Dis. (2005) [Pubmed]
  7. Molecular evolution perspectives on intraspecific lateral DNA transfer of topoisomerase and gyrase loci in Streptococcus pneumoniae, with implications for fluoroquinolone resistance development and spread. Stanhope, M.J., Walsh, S.L., Becker, J.A., Italia, M.J., Ingraham, K.A., Gwynn, M.N., Mathie, T., Poupard, J.A., Miller, L.A., Brown, J.R., Amrine-Madsen, H. Antimicrob. Agents Chemother. (2005) [Pubmed]
  8. Activity of gemifloxacin against quinolone-resistant Streptococcus pneumoniae strains in vitro and in a mouse pneumonia model. Azoulay-Dupuis, E., Bédos, J.P., Mohler, J., Moine, P., Cherbuliez, C., Peytavin, G., Fantin, B., Köhler, T. Antimicrob. Agents Chemother. (2005) [Pubmed]
  9. Intrinsic reduced susceptibility of serotype 6 Streptococcus pyogenes to fluoroquinolone antibiotics. Orscheln, R.C., Johnson, D.R., Olson, S.M., Presti, R.M., Martin, J.M., Kaplan, E.L., Storch, G.A. J. Infect. Dis. (2005) [Pubmed]
  10. Ciprofloxacin dimers target gyrase in Streptococcus pneumoniae. Gould, K.A., Pan, X.S., Kerns, R.J., Fisher, L.M. Antimicrob. Agents Chemother. (2004) [Pubmed]
  11. Selection of a gyrA Mutation and Treatment Failure with Gatifloxacin in a Patient with Streptococcus pneumoniae with a Preexisting parC Mutation. Kays, M.B., Zhanel, G.G., Reimann, M.A., Jacobi, J., Denys, G.A., Smith, D.W., Wack, M.F. Pharmacotherapy (2007) [Pubmed]
  12. Primary targets of fluoroquinolones in Streptococcus pneumoniae. Fukuda, H., Hiramatsu, K. Antimicrob. Agents Chemother. (1999) [Pubmed]
  13. Sparfloxacin resistance in clinical isolates of Streptococcus pneumoniae: involvement of multiple mutations in gyrA and parC genes. Taba, H., Kusano, N. Antimicrob. Agents Chemother. (1998) [Pubmed]
  14. Relationship between mutations in parC and gyrA of clinical isolates of Streptococcus pneumoniae and resistance to ciprofloxacin and grepafloxacin. Stewart, B.A., Johnson, A.P., Woodford, N. J. Med. Microbiol. (1999) [Pubmed]
  15. Fluoroquinolone resistance in Streptococcus pneumoniae in United States since 1994-1995. Brueggemann, A.B., Coffman, S.L., Rhomberg, P., Huynh, H., Almer, L., Nilius, A., Flamm, R., Doern, G.V. Antimicrob. Agents Chemother. (2002) [Pubmed]
  16. Efficacy and pharmacodynamics of simulated human-like treatment with levofloxacin on experimental pneumonia induced with penicillin-resistant pneumococci with various susceptibilities to fluoroquinolones. Croisier, D., Chavanet, P., Lequeu, C., Ahanou, A., Nierlich, A., Neuwirth, C., Piroth, L., Duong, M., Buisson, M., Portier, H. J. Antimicrob. Chemother. (2002) [Pubmed]
  17. Fluoroquinolone Resistance in Streptococcus pneumoniae: Area Under the Concentration-Time Curve/MIC Ratio and Resistance Development with Gatifloxacin, Gemifloxacin, Levofloxacin, and Moxifloxacin. Laplante, K.L., Rybak, M.J., Tsuji, B., Lodise, T.P., Kaatz, G.W. Antimicrob. Agents Chemother. (2007) [Pubmed]
  18. Potent antipneumococcal activity of gemifloxacin is associated with dual targeting of gyrase and topoisomerase IV, an in vivo target preference for gyrase, and enhanced stabilization of cleavable complexes in vitro. Heaton, V.J., Ambler, J.E., Fisher, L.M. Antimicrob. Agents Chemother. (2000) [Pubmed]
  19. Antimicrobial resistance of nasopharyngeal pneumococci from children from day-care centres and orphanages in Russia: results of a unique prospective multicentre study. Stratchounski, L.S., Kozlov, R.S., Appelbaum, P.C., Kretchikova, O.I., Kosowska-Shick, K. Clin. Microbiol. Infect. (2006) [Pubmed]
  20. Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae. Bast, D.J., de Azavedo, J.C., Tam, T.Y., Kilburn, L., Duncan, C., Mandell, L.A., Davidson, R.J., Low, D.E. Antimicrob. Agents Chemother. (2001) [Pubmed]
  21. New Real-Time PCR Assay Using Locked Nucleic Acid Probes To Assess Prevalence of ParC Mutations in Fluoroquinolone-Susceptible Streptococcus pneumoniae Isolates from France. Decousser, J.W., Methlouthi, I., Pina, P., Collignon, A., Allouch, P. Antimicrob. Agents Chemother. (2006) [Pubmed]
  22. Prevalence of gyrA, gyrB, parC, and parE mutations in clinical isolates of Streptococcus pneumoniae with decreased susceptibilities to different fluoroquinolones and originating from Worldwide Surveillance Studies during the 1997-1998 respiratory season. Jones, M.E., Sahm, D.F., Martin, N., Scheuring, S., Heisig, P., Thornsberry, C., Köhrer, K., Schmitz, F.J. Antimicrob. Agents Chemother. (2000) [Pubmed]
  23. A nosocomial outbreak of fluoroquinolone-resistant Streptococcus pneumoniae. Weiss, K., Restieri, C., Gauthier, R., Laverdière, M., McGeer, A., Davidson, R.J., Kilburn, L., Bast, D.J., de Azavedo, J., Low, D.E. Clin. Infect. Dis. (2001) [Pubmed]
  24. The molecular epidemiology of Streptococcus pneumoniae with quinolone resistance mutations. Richter, S.S., Heilmann, K.P., Beekmann, S.E., Miller, N.J., Rice, C.L., Doern, G.V. Clin. Infect. Dis. (2005) [Pubmed]
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