1887

Chapter 65 : Mechanisms of Quinolone Resistance

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in
Zoomout

Mechanisms of Quinolone Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap65-1.gif /docserver/preview/fulltext/10.1128/9781555816513/9781555813437_Chap65-2.gif

Abstract:

With the increasing use of quinolones for the treatment of gram-positive bacterial infections, an understanding of the mechanisms of quinolone resistance in gram-positive bacteria is of considerable importance. This chapter summarizes the current understanding of established mechanisms of resistance to this class of antimicrobial agents in gram-positive bacteria. There are important differences between gram-positive and gram negative bacteria both in target enzyme sensitivity and in the means by which efflux resistance mechanisms operate that are of clinical and fundamental importance. Quinolones interact with both of the two type 2 topoisomerases in eubacteria, DNA gyrase and topoisomerase IV, which are essential for bacterial DNA replication. Quinolone-resistant clinical and laboratory strains of have been shown to have reduced accumulation of quinolones that is reversible with reserpine, suggesting the involvement of an efflux system(s) in quinolone resistance. Quinolone-resistant clinical isolates of viridans streptococci have been shown to have an efflux phenotype defined as lower MICs of quinolones in the presence of reserpine. DNA from such strains of and was able to transform to efflux phenotype in the laboratory. Overexpression of and genes for topoisomerases from plasmids are known, however, to have toxic effects on the cell that may limit the fitness of resistant bacteria containing them. Thus, at present quinolone resistance in gram-positive bacteria is attributable exclusively to chromosomal mutations that affect quinolone targets or quinolone permeation to these targets.

Citation: Hooper D. 2006. Mechanisms of Quinolone Resistance, p 821-849. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch65

Key Concept Ranking

Major Facilitator Superfamily
0.5091003
Bacterial Proteins
0.43186155
Bacterial DNA Replication
0.42421898
0.5091003
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

Figures

Image of FIGURE 1
FIGURE 1

Structures of old and newer quinolones.

Citation: Hooper D. 2006. Mechanisms of Quinolone Resistance, p 821-849. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch65
Permissions and Reprints Request Permissions
Download as Powerpoint

References

/content/book/10.1128/9781555816513.chap65
1. Ackermann, G.,, Y. J. Tang,, R. Kueper,, P. Heisig,, A. C. Rodloff,, J. Silva, Jr.,, and S. H. Cohen. 2001. Resistance to moxifloxacin in toxigenic Clostridium difficile isolates is associated with mutations in gyrA. Antimicrob. Agents Chemother. 45: 2348 2353.
2. Ahmed, M.,, C. M. Borsch,, S. S. Taylor,, N. Vazquez- Laslop,, and A. A. Neyfakh. 1994. A protein that activates expression of a multidrug efflux transporter upon binding the transporter substrates. J. Biol. Chem. 269: 28506 28513.
3. Ahmed, M.,, L. Lyass,, P. N. Markham,, S. S. Taylor,, N. Vazquez-Laslop,, and A. A. Neyfakh. 1995. Two highly similar multidrug transporters of Bacillus subtilis whose expression is differentially regulated. J. Bacteriol. 177: 3904 3910.
4. Alekshun, M. N.,, S. B. Levy,, T. R. Mealy,, B. A. Seaton,, and J. F. Head. 2001. The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat. Struct. Biol. 8: 710 714.
5. Baranova, N. N.,, and A. A. Neyfakh. 1997. Apparent involvement of a multidrug transporter in the fluoroquinolone resistance of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 41: 1396 1398.
6. Bast, D. J.,, J. C. S. De Azavedo,, T. Y. Tam,, L. Kilburn,, C. Duncan,, L. A. Mandell,, R. J. Davidson,, and D. E. Low. 2001. Interspecies recombination contributes minimally to fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45: 2631 2634.
7. Bast, D. J.,, D. E. Low,, C. L. Duncan,, L. Kilburn,, L. A. Mandell,, R. J. Davidson,, and J. C. S. De Azavedo. 2000. Fluoroquinolone resistance in clinical isolates of Streptococcus pneumoniae: contributions of type II topoisomerase mutations and efflux to levels of resistance. Antimicrob. Agents Chemother. 44: 3049 3054.
8. Bates, A. D.,, M. H. O’Dea,, and M. Gellert. 1996. Energy coupling in Escherichia coli DNA gyrase: the relationship between nucleotide binding, strand passage, and DNA supercoiling. Biochemistry 35: 1408 1416.
9. Berger, J. M.,, S. J. Gamblin,, S. C. Harrison,, and J. C. Wang. 1996. Structure and mechanism of DNA topoisomerase II. Nature 379: 225 232.
10. Blanche, F.,, B. Cameron,, F. X. Bernard,, L. Maton,, B. Manse,, L. Ferrero,, N. Ratet,, C. Lecoq,, A. Goniot,, D. Bisch,, and J. Crouzet. 1996. Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases. Antimicrob. Agents Chemother. 40: 2714 2720.
11. Breines, D. M.,, S. Ouabdesselam,, E. Y. Ng,, J. Tankovic,, S. Shah,, C. J. Soussy,, and D. C. Hooper. 1997. Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of parE gene encoding a subunit of topoisomerase IV. Antimicrob. Agents Chemother. 41: 175 179.
12. Brenwald, N. P.,, P. Appelbaum,, T. Davies,, and M. J. Gill. 2003. Evidence for efflux pumps, other than PmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Clin. Microbiol. Infect. 9: 140 143.
13. Brenwald, N. P.,, M. J. Gill,, and R. Wise. 1997. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro susceptibilities of fluoroquinolone-resistant strains of Streptococcus pneumoniae to norfloxacin. J. Antimicrob. Chemother. 40: 458 460.
14. Brenwald, N. P.,, M. J. Gill,, and R. Wise. 1998. Prevalence of a putative efflux mechanism among fluoroquinolone- resistant clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 42: 2032 2035.
15. Brisse, S.,, A. C. Fluit,, U. Wagner,, P. Heisig,, D. Milatovic,, J. Verhoef,, S. Scheuring,, K. Köhrer,, and F. J. Schmitz. 1999. Association of alterations in ParC and GyrA proteins with resistance of clinical isolates of Enterococcus faecium to nine different fluoroquinolones. Antimicrob. Agents Chemother. 43: 2513 2516.
16. Broskey, J.,, K. Coleman,, M. N. Gwynn,, L. McCloskey,, C. Traini,, L. Voelker,, and R. Warren. 2000. Efflux and target mutations as quinolone resistance mechanisms in clinical isolates of Streptococcus pneumoniae. J. Antimicrob. Chemother. 45: 95 99.
17. Crisona, N. J.,, T. R. Strick,, D. Bensimon,, V. Croquette,, and N. R. Cozzarelli. 2000. Preferential relaxation of positively supercoiled DNA by E. coli topoisomerase IV in single-molecule and ensemble measurements. Genes Dev. 14: 2881 2892.
18. Discotto, L. F.,, L. E. Lawrence,, K. L. Denbleyker,, and J. F. Barrett. 2001. Staphylococcus aureus mutants selected by BMS-284756. Antimicrob. Agents Chemother. 45: 3273 3275.
19. Domagala, J. M. 1994. Structure-activity and structureside- effect relationships for the quinolone antibacterials. J. Antimicrob. Chemother. 33: 685 706.
20. Domagala, J. M.,, and S. E. Hagen,. 2003. Structure-activity relationships of the quinolone antibacterials in the new millennium: some things change and some do not, p. 3 18. In D. C. Hooper, and E. Rubinstein (ed.), Quinolone Antimicrobial Agents. ASM Press, Washington, D.C.
21. El Amin, N.,, S. Jalal,, and B. Wretlind. 1999. Alterations in GyrA and ParC associated with fluoroquinolone resistance in Enterococcus faecium. Antimicrob. Agents Chemother. 43: 947 949.
22. Fass, D.,, C. E. Bogden,, and J. M. Berger. 1999. Quaternary changes in topoisomerase II may direct orthogonal movement of two DNA strands. Nature Struct. Biol. 6: 322 326.
23. Ferrero, L.,, B. Cameron,, and J. Crouzet. 1995. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus. Antimicrob. Agents Chemother. 39: 1554 1558.
24. Ferrero, L.,, B. Cameron,, B. Manse,, D. Lagneaux,, J. Crouzet,, A. Famechon,, and F. Blanche. 1994. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones. Mol. Microbiol. 13: 641 653.
25. Fitzgibbon, J. E.,, J. F. John,, J. L. Delucia,, and D. T. Dubin. 1998. Topoisomerase mutations in trovafloxacin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 42: 2122 2124.
26. Fournier, B.,, R. Aras,, and D. C. Hooper. 2000. Expression of the multidrug resistance transporter NorA from Staphylococcus aureus is modified by a two-component regulatory system. J. Bacteriol. 182: 664 671.
27. Fournier, B.,, and D. C. Hooper. 1998. Mutations in topoisomerase IV and DNA gyrase of Staphylococcus aureus: novel pleiotropic effects on quinolone and coumarin activity. Antimicrob. Agents Chemother. 42: 121 128.
28. Fournier, B.,, and D. C. Hooper. 1998. Effects of mutations in GrlA of topoisomerase IV from Staphylococcus aureus on quinolone and coumarin activity. Antimicrob. Agents Chemother. 42: 2109 2112.
29. Fournier, B.,, Q. C. Truong-Bolduc,, X. Zhang,, and D. C. Hooper. 2001. A mutation in the 5' untranslated region increases stability of norA mRNA, encoding a multidrug resistance transporter of Staphylococcus aureus. J. Bacteriol. 183: 2367 2371.
30. Fukuda, H.,, and K. Hiramatsu. 1999. Primary targets of fluoroquinolones in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43: 410 412.
31. Fukuda, H.,, R. Kishii,, M. Takei,, and M. Hosaka. 2001. Contributions of the 8-methoxy group of gatifloxacin to resistance selectivity, target preference, and antibacterial activity against Streptococcus pneumoniae. Antimicrob. Agents Chemother. 45: 1649 1653.
32. Gellert, M. 1981. DNA topoisomerases. Annu. Rev. Biochem. 50: 879 910.
33. Gellert, M.,, K. Mizuuchi,, M. H. O’Dea,, T. Itoh,, and J. I. Tomizawa. 1977. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc. Natl. Acad. Sci. USA 74: 4772 4776.
34. Gill, M. J.,, N. P. Brenwald,, and R. Wise. 1999. Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43: 187 189.
35. González, I.,, M. Georgiou,, F. Alcaide,, D. Balas,, and A. G. de la Campa. 1998. Fluoroquinolone resistance mutations in the parC, parE, and gyrA genes of clinical isolates of viridans group streptococci. Antimicrob. Agents Chemother. 42: 2792 2798.
36. Gootz, T. D.,, R. Zaniewski,, S. Haskell,, B. Schmieder,, J. Tankovic,, D. Girard,, P. Courvalin,, and R. J. Polzer. 1996. Activity of the new fluoroquinolone trovafloxacin (CP-99,219) against DNA gyrase and topoisomerase IV mutants of Streptococcus pneumoniae selected in vitro. Antimicrob. Agents Chemother. 40: 2691 2697.
37. Grinius, L. L.,, and E. B. Goldberg. 1994. Bacterial multidrug resistance is due to a single membrane protein which functions as a drug pump. J. Biol. Chem. 269: 29998 30004.
38. Grkovic, S.,, M. H. Brown,, and R. A. Skurray. 2002. Regulation of bacterial drug export systems. Microbiol. Mol. Biol. Rev. 66: 671 701.
39. Hane, M. W.,, and T. H. Wood. 1969. Escherichia coli K-12 mutants resistant to nalidixic acid: genetic mapping and dominance studies. J. Bacteriol. 99: 238 241.
40. Heaton, V. J.,, J. E. Ambler,, and L. M. Fisher. 2000. 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. Antimicrob. Agents Chemother. 44: 3112 3117.
41. Hori, S.,, Y. Ohshita,, Y. Utsui,, and K. Hiramatsu. 1993. Sequential acquisition of norfloxacin and ofloxacin resistance by methicillin-resistant and -susceptible Staphylococcus aureus. Antimicrob. Agents Chemother. 37: 2278 2284.
42. Hoshino, K.,, A. Kitamura,, I. Morrissey,, K. Sato,, J. Kato,, and H. Ikeda. 1994. Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition. Antimicrob. Agents Chemother. 38: 2623 2627.
43. Hsieh, P. C.,, S. A. Siegel,, B. Rogers,, D. Davis,, and K. Lewis. 1998. Bacteria lacking a multidrug pump: a sensitive tool for drug discovery. Proc. Natl. Acad. Sci. USA 95: 6602 6606.
44. Ince, D.,, R. Aras,, and D. C. Hooper. 1999. Mechanisms and frequency of resistance to moxifloxacin in comparison with ciprofloxacin in Staphylococcus aureus. Drugs 58: 132 133.
45. Ince, D.,, and D. C. Hooper. 2001. Mechanisms and frequency of resistance to gatifloxacin in comparison to AM- 1121 and ciprofloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 45: 2755 2764.
46. Ince, D.,, and D. C. Hooper. 2003. Quinolone resistance due to reduced target enzyme expression. J. Bacteriol. 185: 6883 6892.
47. Ince, D.,, and D. C. Hooper. 2000. Mechanisms and frequency of resistance to premafloxacin in Staphylococcus aureus: novel mutations suggest novel drug-target interactions. Antimicrob. Agents Chemother. 44: 3344 3350.
48. Ince, D.,, X. Zhang,, L. C. Silver,, and D. C. Hooper. 2003. Topoisomerase targeting with and resistance to gemifloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 47: 274 282.
49. Ince, D.,, X. Zhang,, L. C. Silver,, and D. C. Hooper. 2002. Dual targeting of DNA gyrase and topoisomerase IV: target interactions of garenoxacin (BMS-284756, T3811ME), a new desfluoroquinolone. Antimicrob. Agents Chemother. 46: 3370 3380.
50. Ince, D.,, X. M. Zhang,, and D. C. Hooper. 2003. Activity of and resistance to moxifloxacin in Staphylococcus aureus. Antimicrob. Agents Chemother. 47: 1410 1415.
51. Ingavale, S. S.,, W. Van Wamel,, and A. L. Cheung. 2003. Characterization of RAT, an autolysis regulator in Staphylococcus aureus. Mol. Microbiol. 48: 1451 1466.
52. Ito, H.,, H. Yoshida,, M. Bogaki-Shonai,, T. Niga,, H. Hattori,, and S. Nakamura. 1994. Quinolone resistance mutations in the DNA gyrase gyrA and gyrB genes of Staphylococcus aureus. Antimicrob. Agents Chemother. 38: 2014 2023.
53. Janoir, C.,, V. Zeller,, M. D. Kitzis,, N. J. Moreau,, and L. Gutmann. 1996. High-level fluoroquinolone resistance in Streptococcus pneumoniae requires mutations in parC and gyrA. Antimicrob. Agents Chemother. 40: 2760 2764.
54. Jonas, B. M.,, B. E. Murray,, and G. M. Weinstock. 2001. Characterization of emeA, a norA homolog and multidrug resistance efflux pump, in Enterococcus faecalis. Antimicrob. Agents Chemother. 45: 3574 3579.
55. Kaatz, G. W.,, and S. M. Seo. 1995. Inducible NorA-mediated multidrug resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 39: 2650 2655.
56. Kanematsu, E.,, T. Deguchi,, M. Yasuda,, T. Kawamura,, Y. Nishino,, and Y. Kawada. 1998. Alterations in the GyrA subunit of DNA gyrase and the ParC subunit of DNA topoisomerase IV associated with quinolone resistance in Enterococcus faecalis. Antimicrob. Agents Chemother. 42: 433 435.
57. Kato, J.,, Y. Nishimura,, R. Imamura,, H. Niki,, S. Hiraga,, and H. Suzuki. 1990. New topoisomerase essential for chromosome segregation in E. coli. Cell 63: 393 404.
58. Kato, J.,, H. Suzuki,, and H. Ikeda. 1992. Purification and characterization of DNA topoisomerase IV in Escherichia coli. J. Biol. Chem. 267: 25676 25684.
59. Korten, V.,, W. M. Huang,, and B. E. Murray. 1994. Analysis by PCR and direct DNA sequencing of gyrA mutations associated with fluoroquinolone resistance in Enterococcus faecalis. Antimicrob. Agents Chemother. 38: 2091 2094.
60. Luong, T. T.,, S. W. Newell,, and C. Y. Lee. 2003. mgr, a novel global regulator in Staphylococcus aureus. J. Bacteriol. 185: 3703 3710.
61. Margolles, A.,, M. Putman,, H. W. Van Veen,, and W. N. Konings. 1999. The purified and functionally reconstituted multidrug transporter LmrA of Lactococcus lactis mediates the transbilayer movement of specific fluorescent phospholipids. Biochemistry 38: 16298 16306.
62. Markham, P. N. 1999. Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob. Agents Chemother. 43: 988 989.
63. Markham, P. N.,, M. Ahmed,, and A. A. Neyfakh. 1996. The drug-binding activity of the multidrug-responding transcriptional regulator BmrR resides in its C-terminal domain. J. Bacteriol. 178: 1473 1475.
64. Markham, P. N.,, and A. A. Neyfakh. 1996. Inhibition of the multidrug transporter NorA prevents emergence of norfloxacin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 40: 2673 2674.
65. Martínez-Martínez, L.,, A. Pascual,, and G. A. Jacoby. 1998. Quinolone resistance from a transferable plasmid. Lancet 351: 797 799.
66. Mitscher, L. A.,, P. Devasthale,, and R. Zavod,. 1993. Structure-activity relationships, p. 3 51. In D. C. Hooper, and J. S. Wolfson (ed.), Quinolone Antimicrobial Agents. American Society for Microbiology, Washington, D.C.
67. Morais Cabral, J. H.,, A. P. Jackson,, C. V. Smith,, N. Shikotra,, A. Maxwell,, and R. C. Liddington. 1997. Crystal structure of the breakage-reunion domain of DNA gyrase. Nature 388: 903 906.
68. Morrissey, I.,, and J. T. George. 2000. Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones. J. Antimicrob. Chemother. 45: 101 106.
69. Muñoz, R.,, and A. G. de la Campa. 1996. ParC subunit of DNA topoisomerase IV of Streptococcus pneumoniae is a primary target of fluoroquinolones and cooperates with DNA gyrase A subunit in forming resistance phenotype. Antimicrob. Agents Chemother. 40: 2252 2257.
70. Nagai, K.,, T. A. Davies,, B. E. Dewasse,, M. R. Jacobs,, and P. C. Appelbaum. 2001. Single- and multi-step resistance selection study of gemifloxacin compared with trovafloxacin, ciprofloxacin, gatifloxacin and moxifloxacin in Streptococcus pneumoniae. J. Antimicrob. Chemother. 48: 365 374.
71. Nakanishi, N.,, S. Yoshida,, H. Wakebe,, M. Inoue,, and S. Mitsuhashi. 1991. Mechanisms of clinical resistance to fluoroquinolones in Enterococcus faecalis. Antimicrob. Agents Chemother. 35: 1053 1059.
72. Neyfakh, A. A. 1992. The multidrug efflux transporter of Bacillus subtilis is a structural and functional homolog of the Staphylococcus NorA protein. Antimicrob. Agents Chemother. 36: 484 485.
73. Neyfakh, A. A.,, C. M. Borsch,, and G. W. Kaatz. 1993. Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter. Antimicrob. Agents Chemother. 37: 128 129.
74. Ng, E. Y.,, M. Trucksis,, and D. C. Hooper. 1996. Quinolone resistance mutations in topoisomerase IV: relationship of the flqA locus and genetic evidence that topoisomerase IV is the primary target and DNA gyrase the secondary target of fluoroquinolones in Staphylococcus aureus. Antimicrob. Agents Chemother. 40: 1881 1888.
75. Ng, E. Y.,, M. Trucksis,, and D. C. Hooper. 1994. Quinolone resistance mediated by norA: physiologic characterization and relationship to flqB, a quinolone resistance locus on the Staphylococcus aureus chromosome. Antimicrob. Agents Chemother. 38: 1345 1355.
76. Nikaido, H.,, and D. G. Thanassi. 1993. Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as examples. Antimicrob. Agents Chemother. 37: 1393 1399.
77. Ohki, R.,, and M. Murata. 1997. bmr3, a third multidrug transporter gene of Bacillus subtilis. J. Bacteriol. 179: 1423 1427.
78. Ohshita, Y.,, K. Hiramatsu,, and T. Yokota. 1990. A point mutation in norA gene is responsible for quinolone resistance in Staphylococcus aureus. Biochem. Biophys. Res. Commun. 172: 1028 1034.
79. Pan, X. S.,, J. Ambler,, S. Mehtar,, and L. M. Fisher. 1996. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 40: 2321 2326.
80. Pan, X. S.,, and L. M. Fisher. 1996. Cloning and characterization of the parC and parE genes of Streptococcus pneumoniae encoding DNA topoisomerase IV. Role in fluoroquinolone resistance. J. Bacteriol. 178: 4060 4069.
81. Pan, X. S.,, and L. M. Fisher. 1998. DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 42: 2810 2816.
82. Pan, X. S.,, and L. M. Fisher. 1997. Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones. Antimicrob. Agents Chemother. 41: 471 474.
83. Pan, X. S.,, G. Yague,, and L. M. Fisher. 2001. Quinolone resistance mutations in Streptococcus pneumoniae GyrA and ParC proteins: mechanistic insights into quinolone action from enzymatic analysis, intracellular levels, and phenotypes of wild-type and mutant proteins. Antimicrob. Agents Chemother. 45: 3140 3147.
84. Paulsen, I. T.,, M. H. Brown,, T. G. Littlejohn,, B. A. Mitchell,, and R. A. Skurray. 1996. Multidrug resistance proteins QacA and QacB from Staphylococcus aureus: membrane topology and identification of residues involved in substrate specificity. Proc. Natl. Acad. Sci. USA 93: 3630 3635.
85. Perichon, B.,, J. Tankovic,, and P. Courvalin. 1997. Characterization of a mutation in the parE gene that confers fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 41: 1166 1167.
86. Pestova, E.,, J. J. Millichap,, F. Siddiqui,, G. A. Noskin,, and L. R. Peterson. 2002. Non-PmrA-mediated multidrug resistance in Streptococcus pneumoniae. J. Antimicrob. Chemother. 49: 553 556.
87. Piddock, L. J.,, M. M. Johnson,, S. Simjee,, and L. Pumbwe. 2002. Expression of efflux pump gene pmrA in fluoroquinolone-resistant and -susceptible clinical isolates of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 46: 808 812.
88. Putman, M.,, L. A. Koole,, H. W. Van Veen,, and W. N. Konings. 1999. T he secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry 38: 13900 13905.
89. Putman, M.,, H. W. Van Veen,, J. E. Degener,, and W. N. Konings. 2001. The lactococcal secondary multidrug transporter LmrP confers resistance to lincosamides, macrolides, streptogramins and tetracyclines. Microbiology 147: 2873 2880.
90. Putman, M.,, H. W. Van Veen,, and W. N. Konings. 2000. Molecular properties of bacterial multidrug transporters. Microbiol. Mol. Biol. Rev. 64: 672 693.
91. Rolston, K. V.,, S. Frisbee-Hume,, B. M. LeBlanc,, H. Streeter,, and D. H. Ho. 2002. Antimicrobial activity of a novel des-fluoro (6) quinolone, garenoxacin (BMS- 284756), compared to other quinolones, against clinical isolates from cancer patients. Diagn. Microbiol. Infect. Dis. 44: 187 194.
92. Roychoudhury, S.,, C. E. Catrenich,, E. J. McIntosh,, H. D. McKeever,, K. M. Makin,, P. M. Koenigs,, and B. Ledoussal. 2001. Quinolone resistance in staphylococci: activities of new nonfluorinated quinolones against molecular targets in whole cells and clinical isolates. Antimicrob. Agents Chemother. 45: 1115 1120.
93. Schmitz, F. J.,, B. Hofmann,, B. Hansen,, S. Scheuring,, M. Lückefahr,, M. Klootwijk,, J. Verhoef,, A. Fluit,, H. P. Heinz,, K. Köhrer,, and M. E. Jones. 1998. Relationship between ciprofloxacin, ofloxacin, levofloxacin, sparfloxacin and moxifloxacin (BAY 12-8039) MICs and mutations in grlA, grlB, gyrA and gyrB in 116 unrelated clinical isolates of Staphylococcus aureus. J. Antimicrob. Chemother. 41: 481 484.
94. Schmitz, F. J.,, M. E. Jones,, B. Hofmann,, B. Hansen,, S. Scheuring,, M. F. A. Lückefahr,, J. Verhoef,, U. Hadding,, H. P. Heinz,, and K. Köhrer. 1998. Characterization of grlA, grlB, gyrA, and gyrB mutations in 116 unrelated isolates of Staphylococcus aureus and effects of mutations on ciprofloxacin MIC. Antimicrob. Agents Chemother. 42: 1249 1252.
95. Shen, L. L.,, W. E. Kohlbrenner,, D. Weigl,, and J. Baranowski. 1989. Mechanism of quinolone inhibition of DNA gyrase. Appearance of unique norfloxacin binding sites in enzyme-DNA complexes. J. Biol. Chem. 264: 2973 2978.
96. Sreedharan, S.,, M. Oram,, B. Jensen,, L. R. Peterson,, and L. M. Fisher. 1990. DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J. Bacteriol. 172: 7260 7262.
97. Sugino, A.,, C. L. Peebles,, K. N. Kreuzer,, and N. R. Cozzarelli. 1977. 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. Proc. Natl. Acad. Sci. USA 74: 4767 4771.
98. Sun, L.,, S. Sreedharan,, K. Plummer,, and L. M. Fisher. 1996. NorA plasmid resistance to fluoroquinolones: role of copy number and norA frameshift mutations. Antimicrob. Agents Chemother. 40: 1665 1669.
99. Takahata, M.,, M. Yonezawa,, S. Kurose,, N. Futakuchi,, N. Matsubara,, Y. Watanabe,, and H. Narita. 1996. Mutations in the gyrA and grlA genes of quinolone-resistant clinical isolates of methicillin-resistant Staphylococcus aureus. J. Antimicrob. Chemother. 38: 543 546.
100. Takei, M.,, H. Fukuda,, R. Kishii,, and M. Hosaka. 2001. Target preference of 15 quinolones against Staphylococcus aureus, based on antibacterial activities and target inhibition. Antimicrob. Agents Chemother. 45: 3544 3547.
101. Takenouchi, T.,, C. Ishii,, M. Sugawara,, Y. Tokue,, and S. Ohya. 1995. Incidence of various gyrA mutants in 451 Staphylococcus aureus strains isolated in Japan and their susceptibilities to 10 fluoroquinolones. Antimicrob. Agents Chemother. 39: 1414 1418.
102. Tankovic, J.,, F. Mahjoubi,, P. Courvalin,, J. Duval,, and R. Leclercq. 1996. Development of fluoroquinolone resistance in Enterococcus faecalis and role of mutations in the DNA gyrase gyrA gene. Antimicrob. Agents Chemother. 40: 2558 2561.
103. Tran, J. H.,, and G. A. Jacoby. 2002. Mechanism of plasmid- mediated quinolone resistance. Proc. Natl. Acad. Sci. USA 99: 5638 5642.
104. Trucksis, M.,, J. S. Wolfson,, and D. C. Hooper. 1991. A novel locus conferring fluoroquinolone resistance in Staphylococcus aureus. J. Bacteriol. 173: 5854 5860.
104a.. Truong-Bolduc, Q. C.,, P. M. Dunman,, J. Strahilevitz,, S. J. Projan,, and D. C. Hooper. 2005. MgrA is a multiple regulator of two new efflux pumps in Staphylococcus aureus. J. Bacteriol. 187: 2395 2405.
105. Truong-Bolduc, Q. C.,, X. Zhang,, and D. C. Hooper. 2003. Characterization of NorR protein, a multifunctional regulator of norA expression in Staphylococcus aureus. J. Bacteriol. 185: 3127 3138.
106. Van Veen, H. W.,, K. Venema,, H. Bolhuis,, I. Oussenko,, J. Kok,, B. Poolman,, A. J. M. Driessen,, and W. N. Konings. 1996. Multidrug resistance mediated by a bacterial homolog of the human multidrug transporter MDR1. Proc. Natl. Acad. Sci. USA 93: 10668 10672.
107. Varon, E.,, C. Janoir,, M. D. Kitzis,, and L. Gutmann. 1999. ParC and GyrA may be interchangeable initial targets of some fluoroquinolones in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43: 302 306.
108. Wang, J. C. 2002. Cellular roles of DNA topoisomerases: a molecular perspective. Nat. Rev. Mol. Cell Biol. 3: 430 440.
109. Wang, J. C. 1996. DNA topoisomerases. Annu. Rev. Biochem. 65: 635 692.
110. Wang, M. G.,, J. H. Tran,, G. A. Jacoby,, Y. Y. Zhang,, F. Wang,, and D. C. Hooper. 2003. Plasmid-mediated quinolone resistance in clinical isolates of Escherichia coli from Shanghai, China. Antimicrob. Agents Chemother. 47: 2242 2248.
111. Wang, T.,, M. Tanaka,, and K. Sato. 1998. Detection of grlA and gyrA mutations in 344 Staphylococcus aureus strains. Antimicrob. Agents Chemother. 42: 236 240.
112. Wasserman, R. A.,, and J. C. Wang. 1994. Mechanistic studies of amsacrine-resistant derivatives of DNA topoisomerase. II. Implications in resistance to multiple antitumor drugs targeting the enzyme. J. Biol. Chem. 269: 20943 20951.
113. Wetzstein, H. G.,, N. Schmeer,, and W. Karl. 1997. Degradation of the fluoroquinolone enrofloxacin by the brown rot fungus Gloeophyllum striatum: identification of metabolites. Appl. Environ. Microbiol. 63: 4272 4281.
114. Wilkinson, B. J., 1997. Biology, p. 1 38. In K. B. Crossley, and G. L. Archer (ed.), The Staphylococci in Human Disease. Churchill Livingstone, New York, N.Y.
115. Willmott, C. J.,, and A. Maxwell. 1993. A single point mutation in the DNA gyrase A protein greatly reduces binding of fluoroquinolones to the gyrase-DNA complex. Antimicrob. Agents Chemother. 37: 126 127.
116. Woolridge, D. P.,, N. Vazquez-Laslop,, P. N. Markham,, M. S. Chevalier,, E. W. Gerner,, and A. A. Neyfakh. 1997. Efflux of the natural polyamine spermidine facilitated by the Bacillus subtilis multidrug transporter Blt. J. Biol. Chem. 272: 8864 8866.
117. Yamagishi, J. I.,, T. Kojima,, Y. Oyamada,, K. Fujimoto,, H. Hattori,, S. Nakamura,, and M. Inoue. 1996. Alterations in the DNA topoisomerase IV grlA gene responsible for quinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 40: 1157 1163.
118. Yoshida, H.,, M. Bogaki,, S. Nakamura,, K. Ubukata,, and M. Konno. 1990. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J. Bacteriol. 172: 6942 6949.
119. Yu, J. L.,, L. Grinius,, and D. C. Hooper. 2002. NorA functions as a multidrug efflux protein in both cytoplasmic membrane vesicles and reconstituted proteoliposomes. J. Bacteriol. 184: 1370 1377.
120. Zechiedrich, E. L.,, and N. R. Cozzarelli. 1995. Roles of topoisomerase IV and DNA gyrase in DNA unlinking during replication in Escherichia coli. Genes Dev. 9: 2859 2869.
121. Zheleznova, E. E.,, and R. G. Brennan. 2000. Crystal structure of the transcription activator BmrR bound to DNA and a drug. Nature 409: 378 382.
122. Zheleznova, E. E.,, P. N. Markham,, A. A. Neyfakh,, and R. G. Brennan. 1999. Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter. Cell 96: 353 362.

Tables

Generic image for table
TABLE 2

Mutations in the GyrB subunit of DNA gyrase and the ParE subunit of topoisomerase IV associated with quinolone resistance

Rows reflect alignments of homologous amino acids.

Amino acids for which genetic data support a role for the mutation in causing resistance. Other mutant amino acids have been associated with resistance in clinical isolates.

Citation: Hooper D. 2006. Mechanisms of Quinolone Resistance, p 821-849. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch65
Generic image for table
TABLE 1

Mutations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV associated with quinolone resistance

Rows reflect alignments of homologous amino acids.

Amino acids for which genetic data support a role for the mutation in causing resistance. Other mutant amino acids have been associated with resistance in clinical isolates.

Citation: Hooper D. 2006. Mechanisms of Quinolone Resistance, p 821-849. In Fischetti V, Novick R, Ferretti J, Portnoy D, Rood J (ed), Gram-Positive Pathogens, Second Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816513.ch65

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error