1887

Chapter 3 : Mechanisms of Quinolone Resistance

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

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in
Zoomout

Mechanisms of Quinolone Resistance, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817817/9781555812317_Chap03-1.gif /docserver/preview/fulltext/10.1128/9781555817817/9781555812317_Chap03-2.gif

Abstract:

This chapter reviews the mechanisms of quinolone resistance. Initial studies of resistant clinical isolates of prior to the recognition of the role of topoisomerase IV in resistance commonly had GyrA mutations, but when ParC and ParE were also evaluated, GyrA quinolone resistance mutations were not found in the absence of mutations in topoisomerase IV. The strongest genetic data for the secondary role of topoisomerase IV in quinolone resistance is from , in which mutations in ParC or ParE were shown to contribute to resistance only in the presence of mutant GyrA.. The largest body of information concerning the role of topoisomerase IV in quinolone resistance in gram-positive bacteria comes from studies of and . It seems likely that the role of the Mar and Sox regulons and the AcrAB efflux pump in quinolone resistance in serovar will be similar to that in . Although all four known efflux systems in cause increases in resistance to quinolones when overexpressed, quinolone congeners differ in the extent to which they are affected by each system, and use of different quinolones in resistance selections results in differential selection of mutants overexpressing these systems. The two best-studied systems that effect quinolone resistance are NorA of and Bmr and Bit of , but additional examples are being identified and studied in other gram-positive bacteria.

Citation: Hooper D. 2003. Mechanisms of Quinolone Resistance, p 41-67. In Hooper D, Rubinstein E (ed), Quinolone Antimicrobial Agents, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555817817.ch3
Highlighted Text: Show | Hide
Loading full text...

Full text loading...

References

/content/book/10.1128/9781555817817.chap3
1. Ackermann, G.,, Y. J. Tang,, R. Kueper,, P. Heisig,, A. C. Rodloff,, J. SilvaJr.,, and S. H. Cohen. 2001. Resistance to moxifloxacin in toxigenic Clostridium difficile isolates is associated with mutations in gyrA. Antimicrob. Agents Chemother. 45:23482353.
2. Aeschlimann, J. R.,, L. D. Dresser,, G. W. Kaatz,, and M. J. Rybak. 1999. Effects of NorA inhibitors on in vitro antibacterial activities and postantibiotic effects of levofloxacin, ciprofloxacin, and norfloxacin in genetically related strains of Staphylococcus aureus. Antimicrob. Agents Chemother. 43:335340.
3. 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. 269:2850628513.
4. 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. 177:39043910.
5. Akasaka, T.,, M. Tanaka,, A. Yamaguchi,, and K. Sato. 2001. Type II topoisomerase mutations in fluoroquinolone-resistant clinical strains of Pseudomonas aeruginosa isolated in 1998 and 1999: role of target enzyme in mechanism of fluoroquinolone resistance. Antimicrob. Agents Chemother. 45:22632268.
6. Alangaden, G. J.,, E. K. Manavathu,, S. B. Vakulenko,, N. M. Zvonok,, and S. A. Lerner. 1995. Characterization of fluoroquinolone- resistant mutant strains of Mycobacterium tuberculosis selected in the laboratory and isolated from patients. Antimicrob. Agents Chemother. 39:17001703.
7. Alekshun, M. N.,, and S. B. Levy. 1997. Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob. Agents Chemother. 41:20672075.
8. Alonso, A.,, and J. L. Martinez. 2000. Cloning and characterization of SmeDEF, a novel multidrug efflux pump from Stenotrophomonas maltophilia. Antimicrob. Agents Chemother. 44:30793086.
9. Alonso, A.,, and J. L. Martinez. 2001. Expression of multidrug efflux pump SmeDEF by clinical isolates of Stenotrophomonas maltophilia . Antimicrob. Agents Chemother. 45:18791881.
10. Alovero, F. L.,, X . S. Pan,, J. E. Morris,, R. H. Manzo,, and L. M. Fisher. 2000. Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide modifications at C-7 of ciprofloxacin change its primary target in Streptococcus pneumoniae from topoisomerase IV to gyrase. Antimicrob. Agents Chemother. 44:320325.
11. Andersen, J.,, N. Delihas,, K. Ikenaka,, P. J. Green,, O. Pines,, O. Ilercil,, and M. Inouye. 1987. The isolation and characterization of RNA coded by the micF gene in Escherichia coli . Nucleic Acids Res. 15:20892101.
12. Ariza, R. R.,, S. P. Cohen,, N. Bachhawat,, S. B. Levy,, and B. Demple. 1994. Repressor mutations in the marRAB operon that activate oxidative stress genes and multiple antibiotic resistance in Escherichia coli. J. Bacteriol. 176:143148.
13. Bachoual, R.,, L. Dubreuil,, C. J. Soussy,, and J. Tankovic. 2000. Roles of gyrA mutations in resistance of clinical isolates and in vitro mutants of Bacteroides fragilis to the new fluoroquinolone trovafloxacin. Antimicrob. Agents Chemother. 44:18421845.
14. Bagel, S.,, V. Htillen,, B. Wiedemann,, and P. Heisig. 1999. Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. Antimicrob. Agents Chemother. 43:868875.
15. Balague, C.,, and E. G. Vescovi. 2001. Activation of multiple antibiotic resistance in uropathogenic Escherichia coli strains by aryloxoalcanoic acid compounds. Antimicrob. Agents Chemother. 45:18151822.
16. Baranova, N. N.,, and A. A. Neyfakh. 1997. Apparent involvement of a multidrug transporter in the fluoroquinolone resistance of Streptococcus pneumoniae. Antimicrob. Agents Chemother. 41:13961398.
17. Barnard, F. M.,, and A. Maxwell. 2001. Interaction between DNA gyrase and quinolones: effects of alanine mutations at GyrA subunit residues Ser8 3 and Asp8 7. Antimicrob. Agents Chemother. 45:19942000.
18. Bast, D. J.,, J. C. S. De Azavedo,, T. Y. Tarn,, 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. 45:26312634.
19. 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. 44:30493054.
20. Bebear, C. M.,, A. Charron,, J. M. Bove,, C. Bebear,, and J. Renaudin. 1998. Cloning and nucleotide sequences of the topoisomerase IV parC and parE genes of Mycoplasma hominis . Antimicrob. Agents Chemother. 42:20242031.
21. Bebear, C. M.,, H. Renaudin,, A. Charron,, J. M. Bove,, C. Bebear,, and J. Renaudin. 1998. Alterations in topoisomerase IV and DNA gyrase in quinolone-resistant mutants of Mycoplasma hominis obtained in vitro. Antimicrob. Agents Chemother. 42:23042311.
22. Bebear, C. M.,, J. Renaudin,, A. Charron,, H. Renaudin,, B. de Barbeyrac,, T. Schaeverbeke,, and C. Bebear. 1999. Mutations in the gyrA, parC, and parE genes associated with fluoroquinolone resistance in clinical isolates of Mycoplasma hominis. Antimicrob. Agents Chemother. 43: 954956.
23. Belland, R. J.,, S. G. Morrison,, C. Ison,, and W. M. Huang. 1994. Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone-resistant isolates. Mol. Microbiol. 14:371380.
24. Berger, J. M. 1998. Type II DNA topoisomerases. Curr. Opin. Struct. Biol. 8:2632.
25. Berger, J. M.,, S. J. Gamblin,, S. C. Harrison,, and J. C. Wang. 1996. Structure and mechanism of DNA topoisomerase II. Nature 379:225232.
26. Berger, J. M.,, and J. C. Wang. 1996. Recent developments in DNA topoisomerase II structure and mechanism. Curr. Opin. Struct. Biol. 6:8490.
27. 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. 40:27142720.
28. Reference deleted.
29. 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. 41:175179.
30. 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. 40:458460.
31. Brenwald, N. P.,, M. J. Gill,, and R. Wise. 1998. Prevalence of a putative efflux mechanism among fluoroquinoloneresistant clinical isolates of Streptococcus pneumoniae . Antimicrob. Agents Chemother. 42:20322035.
32. Brisse, S.,, A. C. Fluit,, U. Wagner,, P. Heisig,, D. Milatovic,, J. Verhoef,, S. Scheming,, K. Kohrer,, and F. J. Schrnitz. 1999. Association of alterations in ParC and GyrA proteins with resistance of clinical isolates of Enterococcus faecium to nine different fluoroquinolones. Antimicrob. Agents Chemother. 43:25132516.
33. Brisse, S.,, D. Milatovic,, A. C. Fluit,, J. Verhoef,, N. Martin,, S. Scheming,, K. Kohrer,, and F. J. Schmitz. 1999. Comparative in vitro activities of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin against Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, and Enterobacter aerogenes clinical isolates with alterations in GyrA and ParC proteins. Antimicrob. Agents Chemother. 43:20512055.
34. Brooun, A.,, S. Liu,, and K. Lewis. 2000. A dose-response study of antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 44:640646.
35. 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. 45:9599.
36. 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 388:903906.
37. Charvalos, E.,, Y. Tselentis,, M. M. Hamzehpour,, T. Kohler,, and J. C. Pechere. 1995. Evidence for an efflux pump in multidrug- resistant Campylobacter jejuni . Antimicrob. Agents Chemother. 39:20192022.
38. Chou, J. H.,, J. T. Greenberg,, and B. Demple. 1998. Postranscriptional repression of Escherichia coli OmpF protein in response to redox stress: positive control of the micF antisense RNA by the soxRS locus. J. Bacteriol. 175: 10261031.
39. Chuanchuen, R.,, K. Beinlich,, T. T. Hoang,, A. Becher,, R. R. Karkhoff-Schweizer,, and H. P. Schweizer. 2001. Crossresistance between triclosan and antibiotics in Pseudomonas aeruginosa is mediated by multidrug efflux pumps: exposure of a susceptible mutant strain to triclosan selects nfxB mutants overexpressing MexCD-Opr J. Antimicrob. Agents Chemother. 45:428432.
40. Cohen, S. P.,, S. B. Levy,, J. Foulds,, and J. L. Rosner. 1993. Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar -independent pathway. J. Bacteriol. 175:78567862.
41. Cohen, S. P.,, L. M. McMurry,, D. C. Hooper,, J. S. Wolfson,, and S. B. Levy. 1989. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Antimicrob. Agents Chemother. 33:13181325.
42. Cohen, S. P.,, L. M. McMurry,, and S. B. Levy. 1988. marA locus causes decreased expression of OmpF porin in multiple- antibiotic-resistant (Mar) mutants of Escherichia coli. J. Bacteriol. 170:54165422.
43. Cole, S. T.,, R. Brosch,, J. Parkhill,, T. Gamier,, C. Churcher,, D. Harris,, S. V. Gordon,, K. Eiglmeier,, S. Gas,, C. E. Barry,, F. Tekaia,, K. Badcock,, D. Basham,, D. Brown,, T. Chillingworth,, R. Connor,, R. Davies,, K. Devlin,, T. Feltwell,, S. Gentles,, N. Hamlin,, S. Holroyd,, T. Hornsby,, K. Jagels,, and B. G. Barrell. 1998. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393:537544.
44. Cornier, J. A.,, J. A. Fralick,, and A. N. Hamood. 1998. Isolation and characterization of a putative multidrug resistance pump from Vibrio cholerae. Mol. Microbiol. 27:6372.
45. De Kievit, T. R.,, M. D. Parkins,, R. J. Gillis,, R. Srikumar,, H. Ceri,, K. Poole,, B. H. Iglewski,, and D. G. Storey. 2001. Multidrug efflux pumps: expression patterns and contribution to antibiotic resistance in Pseudomonas aeruginosa biofilms. Antimicrob. Agents Chemother. 45:17611770.
46. Deguchi, T.,, A. Fukuoka,, M. Yasuda,, M. Nakano,, S. Ozeki,, E. Kanematsu,, Y. Nishino,, S. Ishihara,, Y. Ban,, and Y. Kawada. 1997. Alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV in quinolone-resistant clinical isolates of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 41:699701.
47. Deguchi, T.,, T. Kawamura,, M. Yasuda,, M. Nakano,, H. Fukuda,, H. Kato,, N. Kato,, Y. Okano,, and Y. Kawada. 1997. In vivo selection of Klebsiella pneumoniae strains with enhanced quinolone resistance during fluoroquinolone treatment of urinary tract infections. Antimicrob. Agents Chemother. 41:16091611.
48. Deguchi, T.,, M. Yasuda,, M. Nakano,, S. Ozeki,, T. Ezaki,, I. Saito,, and Y. Kawada. 1996. Quinolone-resistant Neisseria gonorrhoeae: correlation of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV with antimicrobial susceptibility profiles. Antimicrob. Agents Chemother. 40:10201023.
49. Dessus-Babus, S.,, C. M. Bebear,, A. Charron,, C. Bebear,, and B. de Barbeyrac. 1998. Sequencing of gyrase and topoisomerase IV quinolone-resistance-determining regions of Chlamydia trachomatis and characterization of quinoloneresistant mutants obtained in vitro. Antimicrob. Agents Chemother. 42:24742481.
50. Discotto, L. F.,, L. E. Lawrence,, K. L. Denbleyker,, and J. F. Barrett. 2001. Staphylococcus aureus mutants selected by BMS-284756. Antimicrob. Agents Chemother. 45:32733275.
51. Drlica, K.,, E. C. Engle,, and S. H. Manes. 1980. DNA gyrase on the bacterial chromosome: possibility of two levels of action. Proc. Natl. Acad. Sci. USA 77:68796883.
52. Edgar, R.,, and E. Bibi. 1997. MdfA, an Escherichia coli multidrug resistance protein with an extraordinarily broad spectrum of drug recognition. J. Bacteriol. 179:22742280.
53. El Amin, N.,, S. Jalal,, and B. Wretlind. 1999. Alterations in GyrA and ParC associated with fluoroquinolone resistance in Enterococcus faecium. Antimicrob. Agents Chemother. 43:947949.
54. Evans, K.,, K. Passador,, R. Srikumar,, E. Tsang,, J. Nezezon,, and K. Poole. 1998. Influence of the MexAB-OprM multidrug efflux system on quorum sensing in Pseudomonas aeruginosa. J. Bacteriol. 180:54435447.
55. Ferrero, L.,, B. Cameron,, and J. Crouzet. 1995. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacinresistant mutants of Staphylococcus aureus. Antimicrob. Agents Chemother. 39:15541558.
56. 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. 13:641653.
57. 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: 21222124.
58. 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. 182:664671.
59. 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. 42:21092112.
60. 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. 42:121128.
61. Fournier, B.,, and D. C. Hooper. 2000. A new two-component regulatory system involved in adhesion autolysis, and extracellular proteolytic activity of Staphylococcus aureus. J. Bacteriol. 182:39553964.
62. 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. 183:23672371.
63. Fournier, B.,, X . Zhao,, T. Lu,, K. Drlica,, and D. C. Hooper. 2000. Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus : different patterns of quinolone-induced inhibition of DNA synthesis. Antimicrob. Agents Chemother. 44:21602165.
64. Fralick, J. A. 1996. Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli. J. Bacteriol. 178:58035805.
65. Fraser, C. M.,, S. J. Norris,, G. M. Weinstock,, O. White,, G. G. Sutton,, R. Dodson,, M. Gwinn,, E. K. Hickey,, R. Clayton,, K. A. Ketchum,, E. Sodergren,, J. M. Hardham,, M. P. McLeod,, S. Salzberg,, J. Peterson,, H. Khalak,, D. Richardson,, J. K. Howell,, M. Chidambaram,, T. Utterback,, L. McDonald,, P. Artiach,, C. Bowman,, M. D. Cotton,, and J. C. Venter. 1998. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science 281:375388.
66. Friedman, S. M.,, T. Lu,, and K. Drlica. 2001. Mutation in the DNA gyrase A gene of Escherichia coli that expands the quinolone resistance-determining region. Antimicrob. Agents Chemother. 45:23782380.
67. Fukuda, H.,, and K. Hiramatsu. 1999. Primary targets of fluoroquinolones in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 43:410412.
68. Fukuda, H.,, M. Hosaka,, S. Iyobe,, N. Gotoh,, T. Nishino,, and K. Hirai. 1995. nfxC-type quinolone resistance in a clinical isolate of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 39:790792.
69. 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. 45:16491653.
70. Furukawa, H.,, J. T. Tsay,, S. Jackowski,, Y. Takamura, and C O. Rock. 1993. Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J. Bacteriol. 175:37233729.
71. Gensberg, K.,, Y. F. Jin,, and L. J. Piddock. 1995. A novel gyrB mutation in a fluoroquinolone-resistant clinical isolate of Salmonella typhimurium. FEMS Microbiol. Lett. 132:5760.
72. George, A. M.,, R. M. Hall,, and H. W. Stokes. 1995. Multidrug resistance in Klebsiella pneumoniae: a novel gene, ramA, confers a multidrug resistance phenotype in Escherichia coli . Microbiology 141:19091920.
73. George, A. M.,, and S. B. Levy. 1983. Amplifiable resistance to tetracycline, chloramphenicol, and other antibiotics in Escherichia coli: involvement of a non-plasmid-determined efflux of tetracycline. J. Bacteriol. 155:531540.
74. George, A. M.,, and S. B. Levy. 1983. Gene in the major cotransduction gap of the Escherichia coli K-12 linkage map required for the expression of chromosomal resistance to tetracycline and other antibiotics. J. Bacteriol. 155:541548.
75. Georgiou, M.,, R. Murioz,, F. Roman,, R. Canton,, R. Gomez- Lus,, J. Campos,, and A. G. de la Campa. 1996. Ciprofloxacin-resistant Haemophilus influenzae strains possess mutations in analogous positions of GyrA and ParC. Antimicrob. Agents Chemother. 40:17411744.
76. 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. 43:187189.
77. Giraud, E.,, A. Cloeckaert,, D. Kerboeuf,, and E. Chaslus- Dancla. 2000. Evidence for active efflux as the primary mechanism of resistance to ciprofloxacin in Salmonella enterica serovar Typhimurium. Antimicrob. Agents Chemother. 44:12231228.
78. Gonzalez, 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. 42:27922798.
79. 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. 40:26912697.
80. 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. 269:2999830004.
81. Gustafson, J. E.,, P. V. Candelaria,, S. A. Fisher,, J. P. Goodridge,, T. M. Lichocik,, T. M. McWilliams,, C. T. Price,, F. G. O'Brien,, and W. B. Grubb. 1999. Growth in the presence of salicylate increases fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 43:990992.
82. Hagman, K. E.,, W. Pan,, B. G. Spratt,, J. T. Balthazar,, R. C. Judd,, and W. M. Shafer. 1995. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system. Microbiology 141: 611622.
83. 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. 44:31123117.
84. Heisig, P. 1996. Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli. Antimicrob. Agents Chemother. 40:879885.
85. Hiasa, H.,, D. O. Yousef,, and K. J. Marians. 1996. DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary complex. J. Biol. Chem. 271:2642426429.
86. Hirai, K.,, H. Aoyama,, T. Irikura,, S. Iyobe,, and S. Mitsuhashi. 1986. Differences in susceptibility to quinolones of outer membrane mutants of Salmonella typhimurium and Escherichia coli. Antimicrob. Agents Chemother. 29:535538.
87. Hirai, K.,, S. Suzue,, T. Irikura,, S. Iyobe,, and S. Mitsuhashi. 1987. Mutations producing resistance to norfloxacin in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 31:582586.
88. Hooper, D. C. 1998. Bacterial topoisomerases, anti-topoisomerases, and anti-topoisomerase resistance. Clin. Infect. Dis. 27:S54S63.
89. Hooper, D. C. 1999. Mechanisms of quinolone resistance. Drug Resist. Updates 2:3855.
90. Hooper, D. C.,, J. S. Wolfson,, K. S. Souza,, E. Y. Ng,, G. L. McHugh,, and M. N. Swartz. 1989. Mechanisms of quinolone resistance in Escherichia coli: characterization of nfxB and cfxB, two mutant resistance loci decreasing norfloxacin accumulation. Antimicrob. Agents Chemother. 33:283290.
91. 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. 37:22782284.
92. 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. 38:26232627.
92a. Hsieh, P. C.,, S. A. Siegel,, B. Rogers,, D. Davis,, and K. Lewis. 1998. Bacteria lacking a multidrug efflux pump: a sensitive tool for drug discovery. Proc. Natl. Acad. Sci. USA 95:66026606.
93. Ince, D.,, R. Aras,, and D. C. Hooper. 1999. Mechanisms and frequency of resistance to moxifloxacin in comparison with ciprofloxacin in Staphylococcus aureus . Drugs 58:132133.
94. 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. 44:33443350.
95. 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. 45:27552764.
96. Ishida, H.,, H. Fuziwara,, Y. Kaibori,, T. Horiuchi,, K. Sato,, and Y. Osada. 1995. Cloning of multidrug resistance gene pqrA from Proteus vulgaris . Antimicrob. Agents Chemother. 39:453-457.
97. 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. 38:20142023.
98. Jalal, S.,, O. Ciofu,, N. Hoiby,, N. Gotoh,, and B. Wretlind. 2000. Molecular mechanisms of fluoroquinolone resistance in Pseudomonas aeruginosa isolates from cystic fibrosis patients. Antimicrob. Agents Chemother. 44:710712.
99. Janoir, C.,, E. Varon,, M. D. Kitzis,, and L. Gutmann. 2001. New mutation in ParE in a pneumococcal in vitro mutant resistant to fluoroquinolones. Antimicrob. Agents Chemother. 45:952955.
100. 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. 40:27602764.
101. Kaatz, G. W.,, and S. M. Seo. 1995. Inducible NorA-mediated multidrug resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 39:26502655.
102. 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: 433435.
103. Kern, W. V.,, M. Oethinger,, A. S. Jellen-Ritter,, and S. B. Levy. 2000. Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli. Antimicrob. Agents Chemother. 44:814820.
104. Khodursky, A. B.,, E. L. Zechiedrich,, and N. R. Cozzarelli. 1995. Topoisomerase IV is a target of quinolones in Escherichia coli . Proc. Natl. Acad. Sci. USA 92:1180111805.
105. Kocagoz, T.,, C. J. Hackbarth,, I. Unsal,, E. Y . Rosenberg,, H. Nikaido,, and H. F. Chambers. 1996. Gyrase mutations in laboratory-selected, fluoroquinolone- resistant mutants of Mycobacterium tuberculosis H37Ra. Antimicrob. Agents Chemother. 40:17681774.
106. Kohler, T.,, M. Kok,, M. Michea-Hamzehpour,, P. Plesiat,, N. Gotoh,, T. Nishino,, L. K. Curty,, and J. C. Pechere. 1996. Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40:22882290.
107. Kohler, T.,, M. Michea-Hamzehpour,, U. Henze,, N. Gotoh,, L. Curty,, and J. C. Pechere. 1997. Characterization of MexE-MexF-OprN, a positively regulated multidrug efflux system of Pseudomonas aeruginosa. Mol. Microbiol. 23:345354.
108. Kohler, T.,, M. Michea-Hamzehpour,, P. Plesiat,, A. L. Kahr,, and J. C. Pechere. 1997. Differential selection of multidrug efflux systems by quinolones in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 41:25402543.
109. Kohler, T.,, C. Van Delden,, L. K. Curty,, M. M. Hamzehpour,, and J. C. Pechere. 2001. Overexpression of the MexEFOprN multidrug efflux system affects cell-to-cell signaling in Pseudomonas aeruginosa. J. Bacteriol. 183:52135222.
110. 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. 38:20912094.
111. Koutsolioutsou, A.,, E. A. Martins,, D. G. White,, S. B. Levy,, and B. Demple. 2001. A sox RS-constitutive mutation contributing to antibiotic resistance in a clinical isolate of Salmonella enterica (serovar Typhimurium). Antimicrob. Agents Chemother. 45:3843.
112. Lee, E. H.,, E. Collatz,, I. Podglajen,, and L. Gutmann. 1996. A rob-like gene of Enterobacter cloacae affecting porin synthesis and susceptibility to multiple antibiotics. Antimicrob. Agents Chemother. 40:20292033.
113. Lewis, K.,, D. C. Hooper,, and M. Ouellette. 1997. Multidrug resistance pumps provide broad defense. ASM News 63:605610.
114. Li, X . Z.,, D. M. Livermore,, and H. Nikaido. 1994. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob. Agents Chemother. 38:17321741.
115. Li, X . Z.,, H. Nikaido,, and K. Poole. 1995. Role of mexAmexB- oprM in antibiotic efflux in Pseudomonas aeruginosa . Antimicrob. Agents Chemother. 39:19481953.
116. Li, X . Z.,, L. Zhang,, and K. Poole. 2000. Interplay between the MexA-MexB-OprM multidrug efflux system and the outer membrane barrier in the multiple antibiotic resistance of Pseudomonas aeruginosa. J. Antimicrob. Chemother. 45:433436.
117. Linde, H. J.,, F. Notka,, M. Metz,, B. Kochanowski,, P. Heisig,, and N. Lehn. 2000. In vivo increase in resistance to ciprofloxacin in Escherichia coli associated with deletion of the C-terminal part of MarR. Antimicrob. Agents Chemother. 44:18651868.
118. Liu, J.,, H. E. Takiff,, and H. Nikaido. 1996. Active efflux of fluoroquinolones in Mycobacterium smegmatis mediated by LfrA, a multidrug efflux pump. J. Bacteriol. 178:37913795.
119. Lomovskaya, O.,, F. Kawai,, and A. Matin. 1996. Differential regulation of the mcb and emr operons of Escherichia coli: role of mcb in multidrug resistance. Antimicrob. Agents Chemother. 40:10501052.
120. Lomovskaya, O.,, A. Lee,, K. Hoshino,, H. Ishida,, A. Mistry,, M. S. Warren,, E. Boyer,, S. Chamberland,, and V. J. Lee.1999. Use of a genetic approach to evaluate the consequences of inhibition of efflux pumps in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 43:13401346.
121. Lomovskaya, O.,, and K. Lewis. 1992. emr, an Escherichia coli locus for multidrug resistance. Proc. Natl. Acad. Sci. USA 89:89388942.
122. Lomovskaya, O.,, K. Lewis,, and A. Matin. 1995. EmrR is a negative regulator of the Escherichia coli multidrug resistance pump EmrAB. J. Bacteriol. 177:23282334.
123. Lomovskaya, O.,, M. S. Warren,, A. Lee,, J. Galazzo,, R. Fronko,, M. Lee,, J. Blais,, D. Cho,, S. Chamberland,, T. Renau,, R. Leger,, S. Hecker,, W. Watkins,, K. Hoshino,, H. Ishida,, and V. J. Lee. 2001. Identification and characterization of inhibitors of multidrug resistance efflux pumps in Pseudomonas aeruginosa: novel agents for combination therapy. Antimicrob. Agents Chemother. 45:105116.
124. Mao, W. M.,, M. S. Warren,, A. Lee,, A. Mistry,, and O. Lomovskaya. 2001. MexXY-OprM efflux pump is required for antagonism of aminoglycosides by divalent cations in Pseudomonas aeruginosa . Antimicrob. Agents Chemother. 45:20012007.
125. 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 38:1629816306.
126. Markham, P. N. 1999. Inhibition of the emergence of ciprofloxacin resistance in Streptococcus pneumoniae by the multidrug efflux inhibitor reserpine. Antimicrob. Agents Chemother. 43:988989.
127. 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. 178:14731475.
128. 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. 40:26732674.
129. Martinez-Martinez, L.,, I. Garcia,, S. Ballesta,, V. J. Benedi,, S. Hernandez-Alles,, and A. Pascual. 1998. Energy-dependent accumulation of fluoroquinolones in quinolone-resistant Klebsiella pneumoniae strains. Antimicrob. Agents Chemother. 42:18501852.
130. Martinez-Martinez, L.,, A. Pascual,, and G. A. Jacoby. 1998. Quinolone resistance from a transferable plasmid. Lancet 351:797799.
131. Maseda, H.,, K. Saito,, A. Nakajima,, and T. Nakae. 2000. Variation of the mexT gene, a regulator of the MexEF-OprN efflux pump expression in wild-type strains of Pseudomonas aeruginosa. FEMS Microbiol. Lett. 192:107112.
132. Maseda, H.,, H. Yoneyama,, and T. Nakae. 2000. Assignment of the substrate-selective subunits of the MexEFOprN multidrug efflux pump of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44:658664.
133. Masuda, N.,, and S. Ohya. 1992. Cross-resistance to meropenem, cephems, and quinolones in Pseudomonas aeruginosa . Antimicrob. Agents Chemother. 36:18471851.
134. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, and T. Nishino. 2001. Hypersusceptibility of the Pseudomonas aeruginosa nfxB mutant to 0-lactams due to reduced expression of the AmpC 0-lactamase. Antimicrob. Agents Chemother. 45:12841286.
135. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, H. Tsujimoto,, and T. Nishino. 2000. Contribution of the MexX-MexY-OprM efflux system to intrinsic resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44:22422246.
136. Masuda, N.,, E. Sakagawa,, S. Ohya,, N. Gotoh,, H. Tsujimoto,, and T. Nishino. 2000. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-OprM efflux pumps in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44:33223327.
137. Mazzariol, A.,, Y. Tokue,, T. M. Kanegawa,, G. Cornaglia,, and H. Nikaido. 2000. High-level fluoroquinolone-resistant clinical isolates of Escherichia coli overproduce multidrug efflux protein AcrA. Antimicrob. Agents Chemother. 44:34413443.
138. Miller, P. F.,, L. Gambino,, M. C. Sulavik,, and S. J. Gracheck. 1994. Genetic relationship between soxRS and mar loci in promoting multiple antibiotic resistance in Escherichia coli. Antimicrob. Agents Chemother. 38:17731779.
139. Mine, T.,, Y. Morita,, A. Kataoka,, T. Mizushima,, and T. Tsuchiya. 1999. Expression in Escherichia coli of a new multidrug efflux pump, MexXY, from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 43:415417.
140. Miyamae, S., H, Nikaido, Y. Tanaka, and F. Yoshimura. 1998. Active efflux of norfloxacin by Bacteroides fragilis. Antimicrob. Agents Chemother. 42:21192121.
141. Miyamae, S.,, O. Ueda,, F. Yoshimura,, J. Hwang,, Y. Tanaka,, and H. Nikaido. 2001. A MATE family multidrug efflux transporter pumps out fluoroquinolones in Bacteroides thetaiotaomicron. Antimicrob. Agents Chemother. 45: 33413346.
142. Moore, R. A.,, B. Beckthold,, S. Wong,, A. Kureishi,, and L. E. Bryan. 1995. Nucleotide sequence of the gyrA gene and characterization of ciprofloxacin-resistant mutants of Helicobacter pylori. Antimicrob. Agents Chemother. 39:107111.
143. Morita, Y .,, K. Kodama,, S. Shiota,, T. Mine,, A. Kataoka,, T. Mizushima,, and T. Tsuchiya. 1998. NorM, a putative multidrug efflux protein, of Vibrio parahaemolyticus and its homolog in Escherichia coli. Antimicrob. Agents Chemother. 42:17781782.
144. Morrissey, I.,, and J. T. George. 2000. Purification of pneumococcal type II topoisomerases and inhibition by gemifloxacin and other quinolones. J. Antimicrob. Chemother. 45:101106.
145. Munoz, 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. 40:22522257.
146. Munoz-Bellido, J. L.,, M. A. Manzanares,, J. A. Andres,, M. N. Zufiaurre,, G. Ortiz,, M. S. Hernandez,, and J. A. Garcia- Rodriguez. 1999. Efflux pump-mediated quinolone resistance in Staphylococcus aureus strains wild type for gyrA, gyrB, grlA, and norA . Antimicrob. Agents Chemother. 43:354356.
147. 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. 48:365374.
148. Nagai, K.,, T. A. Davies,, G. A. Pankuch,, B. E. Dewasse,, M. R. Jacobs,, and P. C. Appelbaum. 2000. In vitro selection of resistance to clinafloxacin, ciprofloxacin, and trovafloxacin in Streptococcus pneumoniae. Antimicrob. Agents Chemother. 44:27402746.
149. Nakanishi, N.,, S. Yoshida,, H. Wakebe,, M. Inoue,, and S. Mitsuhashi. 1991. Mechanisms of clinical resistance to fluoroquinolones in Enterococcus faecalis. Antimicrob. Agents Chemother. 35:10531059.
150. Nakano, M.,, T. Deguchi,, T. Kawamura,, M. Yasuda,, M. Kimura,, Y. Okano,, and Y. Kawada. 1997. Mutations in gyrA and parC genes in fluoroquinolone-resistant clinical isolates of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 41:22892291.
151. 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. 36:484485.
152. 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. 37:128129.
153. 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. 38:13451355.
154. 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. 40:18811888.
155. 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. 37:13931399.
156. Nishino, Y.,, T. Deguchi,, M. Yasuda,, T. Kawamura,, M. Nakano,, E. Kanematsu,, S. Ozeki,, and Y. Kawada. 1997. Mutations in the gyrA and parC genes associated with fluoroquinolone resistance in clinical isolates of Citrobacter freundii. FEMS Microbiol. Lett. 154:409414.
157. Oethinger, M.,, W. V. Kern,, A. S. Jellen-Ritter,, L. M. McMurry,, and S. B. Levy. 2000. Ineffectiveness of topoisomerase mutations in mediating clinically significant fluoroquinolone resistance in Escherichia coli in the absence of the AcrAB efflux pump. Antimicrob. Agents Chemother. 44:1013.
158. Oethinger, M.,, I. Podglajen,, W. V. Kern,, and S. B. Levy. 1998. Overexpression of the marA or soxS regulatory gene in clinical topoisomerase mutants of Escherichia coli . Antimicrob. Agents Chemother. 42:20892094.
159. Ohki, R.,, and M. Murata. 1997. bmr3, a third multidrug transporter gene of Bacillus subtilis. J. Bacteriol. 179:14231427.
160. 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. 172:10281034.
161. Okazaki, T.,, and K. Hirai. 1992. Cloning and nucleotide sequence of the Pseudomonas aeruginosa nfxB gene, conferring resistance to new quinolones. FEMS Microbiol. Lett. 76:197202.
162. Okuda, J.,, E. Hayakawa,, M. Nishibuchi,, and T. Nishino. 1999. Sequence analysis of the gyrA and parC homologues of a wild-type strain of Vibrio parahaemolyticus and its fluoroquinolone-resistant mutants. Antimicrob. Agents Chemother. 43:11561162.
163. Okusu, H.,, D. Ma,, and H. Nikaido. 1996. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants.J. Bacteriol. 178:306308.
164. Onodera, Y.,, and K. Sato. 1999. Molecular cloning of the gyrA and gyrB genes of Bacteroides fragilis encoding DNA gyrase. Antimicrob. Agents Chemother. 43:24232429.
165. 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. 40:23212326.
166. 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. 178:40604069.
167. 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. 41:471474.
168. 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. 42:28102816.
169. 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. 45:31403147.
170. 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: 36303635.
171. Paulsen, I. T.,, M. H. Brown,, and R. A. Skurray. 1996. Proton-dependent multidrug efflux systems. Microbiol. Rev. 60:575608.
172. Pearson, J. P.,, C. Van Delden,, and B. H. Iglewski. 1999. Active efflux and diffusion are involved in transport of Pseudomonas aeruginosa cell-to-cell signals. J. Bacteriol. 181:12031210.
173. 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. 41:11661167.
174. Pesci, E. C.,, J. B. Milbank,, J. P. Pearson,, S. McKnight,, A. S. Kende,, E. P. Greenberg,, and B. H. Iglewski. 1999. Quinolone signaling in the cell-to-cell communication system of Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 96:1122911234.
175. Pestova, E.,, R. Beyer,, N. P. Cianciotto,, G. A. Noskin,, and L. R. Peterson. 1999. Contribution of topoisomerase IV and DNA gyrase mutations in Streptococcus pneumoniae to resistance to novel fluoroquinolones. Antimicrob. Agents Chemother. 43:20002004.
176. Piddock, L. J., , and R. Wise. 1986. The effect of altered porin expression in Escherichia coli upon susceptibility to 4- quinolones. J. Antimicrob. Chemother. 18:547549.
177. Piddock, L. J. V.,, D. G. White,, K. Gensberg,, L. Pumbwe,, and D. J. Griggs. 2000. Evidence for an efflux pump mediating multiple antibiotic resistance in Salmonella enterica serovar Typhimurium. Antimicrob. Agents Chemother. 44:31183121.
178. Poole, K. 1994. Bacterial multidrug resistance—emphasis on efflux mechanisms and Pseudomonas aeruginosa. J. Anti microb. Chemother. 34:453456.
179. Poole, K. 2000. Efflux-mediated resistance to fluoroquinolones in gram-negative bacteria. Antimicrob. Agents Chemother, 44:22332241.
180. Poole, K. 2000. Efflux-mediated resistance to fluoroquinolones in gram-positive bacteria and the mycobacteria. Antimicrob. Agents Chemother. 44:25952599.
181. Poole, K.,, N. Gotoh,, H. Tsujimoto,, Q. X. Zhao,, A. Wada,, T. Yamasaki,, S. Neshat,, J. I. Yamagishi,, X . Z. Li,, and T. Nishino. 1996. Overexpression of the mexC-mexD-opr] efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa. Mol. Microbiol. 21:713724.
182. Poole, K.,, K. Krebes,, C. McNally,, and S. Neshat. 1993. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon. J. Bacteriol. 17'5:73637372.
183. Poole, K.,, K. Tetro,, Q. X. Zhao,, S. Neshat,, D. E. Heinrichs,, and N. Bianco. 1996. Expression of the multidrug resistance operon mexA-mexB-oprM in Pseudomonas aeruginosa: mexR encodes a regulator of operon expression. Antimicrob. Agents Chemother. 40:20212028.
184. Pumbwe, L.,, and L. J. V. Piddock. 2000. Two efflux systems expressed simultaneously in multidrug-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44:28612864.
185. Putman, M.,, L. A. Koole,, H. W. Van Veen,, and W. N. Konings. 1999. The secondary multidrug transporter LmrP contains multiple drug interaction sites. Biochemistry 38:1390013905.
186. 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 147:28732880.
187. Putman, M.,, H. W. Van Veen,, and W. N. Konings. 2000. Molecular properties of bacterial multidrug transporters. Microbiol. Mol. Biol. Rev. 64:672693.
188. Rahman, M.,, G. Mauff,, J. Levy,, M. Couturier,, G. Pulverer,, N. Glasdorff,, and J. P. Butzler. 1994. Detection of 4- quinolone resistance mutation in gyrA gene of Shigella dysenteriae type 1 by PCR. Antimicrob. Agents Chemother. 38:24882491.
189. Rella, M.,, and D. Haas. 1982. Resistance of Pseudomonas aeruginosa PAO to nalidixic acid and low levels of beta-lactam antibiotics: mapping of chromosomal genes. Antimicrob. Agents Chemother. 22:242249.
190. Renau, T. E.,, R. Leger,, E. M. Flamme,, J. Sangalang,, M. W. She,, R. Yen,, C. L. Gannon,, D. Griffith,, S. Chamberland,, O. Lomovskaya,, S. J. Hecker,, V. J. Lee,, T. Ohta,, and K. Nakayama. 1999. Inhibitors of efflux pumps in Pseudomonas aeruginosa potentiate the activity of the fluoroquinolone antibacterial levofloxacin.J. Med. Chem. 42:49284931.
191. Revel, V.,, E. Cambau,, V. Jarlier,, and W. Sougakoff. 1994. Characterization of mutations in Mycobacterium smegmatis involved in resistance to fluoroquinolones. Antimicrob. Agents Chemother. 38:19911996.
192. Reyna, F.,, M. Huesca,, V. Gonzalez,, and L. Y. Fuchs. 1995. Salmonella typhimurium gyrA mutations associated with fluoroquinolone resistance. Antimicrob. Agents Chemother. 39:16211623.
193. Robillard, N. J.,, and A. L. Scarpa. 1988. Genetic and physiological characterization of ciprofloxacin resistance in Pseudomonas aeruginosa PAO. Antimicrob. Agents Chemother. 32:535539.
194. 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. 45:11151120.
195. Sabourin, M.,, J. A. Byl,, S. E. Hannah,, J. L. Nitiss,, and N. Osheroff. 1998. A mutant yeast topoisomerase II (top2G437S) with differential sensitivity to anticancer drugs in the presence and absence of ATP. J. Biol. Chem. 273:2908629092.
196. San, M. J.,, C. Hernandez-Chico,, P. Pereda,, and F. Moreno. 1985. Cloning and mapping of the genetic determinants for microcin B17 production and immunity. J. Bacteriol. 163:275281.
197. Sander, P.,, E. De Rossi,, B. Boddinghaus,, R. Cantoni,, M. Branzoni,, E. C. Bottger,, H. Takiff,, R. Rodriguez,, G. Lopez,, and G. Riccardi. 2000. Contribution of the multidrug efflux pump LfrA to innate mycobacterial drug resistance. FEMS Microbiol. Lett. 193:1923.
198. Senior, S.,, A. Schmidt,, E. Maier,, R. Benz,, W. Goebel,, and I. Gentschev. 1997. In vivo and in vitro studies on interactions between the components of the hemolysin (HlyA) secretion machinery of Escherichia coli. Mol. Gen. Genet. 256:306319.
199. Schmitz, F. J.,, A. C. Fluit,, M. Luckefahr,, B. Engler,, B. Hofmann,, J. Verhoef,, H. P. Heinz,, U. Hadding,, and M. E. Jones. 1998. The effect of reserpine, an inhibitor of multidrug efflux pumps, on the in-vitro activities of ciprofloxacin, sparfloxacin and moxifloxacin against clinical isolates of Staphylococcus aureus . J. Antimicrob. Chemother. 42:807810.
200. Schmitz, F. J.,, B. Hertel,, S. Scheuring,, J. Verhoef,, and A. C. Fluit. 1998. Correlation of norfloxacin MIC-values with mutations with the coding and promoter region of the norA gene in 42 unrelated clinical isolates of Staphylococcus aureus. J. Antimicrob. Chemother. 42:561563.
201. Schmitz, F. J.,, B. Hofmann,, B. Hansen,, S. Scheuring,, M. Luckefahr,, M. Klootwijk,, J. Verhoef,, A. Fluit,, H. P. Heinz,, K. Kohrer,, 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. 41:481484.
202. Schmitz, F. J.,, M. E. Jones,, B. Hofmann,, B. Hansen,, S. Scheuring,, M. F. A. Luckefahr,, J. Verhoef,, U. Hadding,, H. P. Heinz,, and K. Kohrer. 1998. Characterization of grlA, grlBt gyrA, and gyrB mutations in 116 unrelated isolates of Staphylococcus aureus and effects of mutations on ciprofloxacin MIC. Antimicrob. Agents Chemother. 42:12491252.
203. 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. 264:29732978.
204. Shultz, T. R.,, J. W. Tapsall,, and P. A. White. 2001. Correlation of in vitro susceptibilities to newer quinolones of naturally occurring quinolone-resistant Neisseria gonorrhoeae strains with changes in GyrA and ParC. Antimicrob. Agents Chemother. 45:734738.
205. 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. 172:72607262.
206. Srikumar, R.,, X . Z. Li,, and K. Poole. 1997. Inner membrane efflux components are responsible for p-lactam specificity of multidrug efflux pumps in Pseudomonas aeruginosa. J. Bacteriol. 179:78757881.
207. Sulavik, M. C.,, M. Dazer,, and P. F. Miller. 1997. The Salmonella typhimurium mar locus: molecular and genetic analyses and assessment of the requirement for virulence. J. Bacteriol. 179:18571866.
208. Sulavik, M. C.,, C. Houseweart,, C. Cramer,, N. Jiwani,, N. Murgolo,, J. Greene,, B. DiDomenico,, K. J. Shaw,, G. H. Miller,, R. Hare,, and G. Shimer. 2001. Antibiotic susceptibility profiles of Escherichia coli strains lacking multidrug efflux pump genes. Antimicrob. Agents Chemother. 45:11261136.
209. 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. 40:16651669.
210. 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. 38:543546.
211. Takei, M.,, H. Fukuda,, R. Kishii,, and M. Hosaka. 2001. Target preference of 15 quinolones against Staphylococcus aureuSy based on antibacterial activities and target inhibition. Antimicrob. Agents Chemother. 45:35443547.
212. 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. 39:14141418.
213. Takiff, H. E.,, M. Cimino,, M. C. Musso,, T. Weisbrod,, R. Martinez,, M. B. Delgado,, L. Salazar,, B. R. Bloom,, and W. R. Jacobs, Jr. 1996. Efflux pump of the proton antiporter family confers low-level fluoroquinolone resistance in Mycobacterium smegmatis. Proc. Natl. Acad. Sci. USA 93:362366.
214. Takiff, H. E.,, L. Salazar,, C. Guerrero,, W. Philipp,, W. M. Huang,, B. Kreiswirth,, S. T. Cole,, W. R. Jacobs, Jr.,, and A. Telenti. 1994. Cloning and nucleotide sequence of Mycobacterium tuberculosis gyrA and gyrB genes and detection of quinolone resistance mutations. Antimicrob. Agents Chemother. 38:773780.
215. Tanaka, M.,, Y. Onodera,, Y. Uchida,, and K. Sato. 1998. Quinolone resistance mutations in the GrlB protein of Staphylococcus aureus. Antimicrob. Agents Chemother. 42:30443046.
216. Tanaka, M.,, Y. Onodera,, Y. Uchida,, K. Sato,, and I. Hayakawa. 1997. Inhibitory activities of quinolones against DNA gyrase and topoisomerase IV purified from Staphylococcus aureus. Antimicrob. Agents Chemother. 41:23622366.
217. Tanaka, T.,, T. Horii,, K. Shibayama,, K. Sato,, S. Ohsuka,, Y. Arakawa,, K. Yamaki,, K. Takagi,, and M. Ohta. 1997. RobA-induced multiple antibiotic resistance largely depends on the activation of the AcrAB efflux. Microbiol. Immunol. 41:697702.
218. 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. 40:25582561.
219. Tankovic, J.,, B. Perichon,, J. Duval,, and P. Courvalin. 1996. Contribution of mutations in gyrA and parC genes to fluoroquinolone resistance of mutants of Streptococcus pneumoniae obtained in vivo and in vitro. Antimicrob. Agents Chemother. 40:25052510.
220. Tavio, M. D.,, J. Vila,, J. Ruiz,, G. Amicosante,, N. Franceschini,, A. M. Martin-Sanchez,, and M. T. J. De Anta. 2000. In vitro selected fluoroquinolone-resistant mutants of Citrobacter freundii: analysis of the quinolone resistance acquisition. J. Antimicrob. Chemother. 45:521524.
221. Taylor, D. E.,, and A. S. S. Chau. 1997. Cloning and nucleotide sequence of the gyrA gene from Campylobacter fetus subsp fetus ATCC 27374 and characterization of ciprofloxacin-resistant laboratory and clinical isolates. Antimicrob. Agents Chemother. 41:665671.
221a. Tran, J. H.,, and G. A. Jacoby. 2002. Mechanism of plasmid-mediated quinolone resistance. Proc. Natl. Acad. Sci. USA 99:56385642.
222. Trees, D. L.,, A. L. Sandul,, W. L. Whittington,, and J. S. Knapp. 1998. Identification of novel mutation patterns in the parC gene of ciprofloxacin-resistant isolates of Neisseria gonorrhoeae . Antimicrob. Agents Chemother. 42:21032105.
222a. 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. 185:31273138.