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Planta Med 2001; 67(1): 3-12
DOI: 10.1055/s-2001-10635
Review

© Georg Thieme Verlag Stuttgart · New York

Inhibitors of Bacterial Topoisomerases: Mechanisms of Action and Resistance and Clinical Aspects1 []

Peter Heisig
  • Pharmazeutische Biologie Universität Hamburg, Hamburg, Germany
Weitere Informationen

Publikationsverlauf

May 26, 2000

August 19, 2000

Publikationsdatum:
31. Dezember 2001 (online)

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Abstract

The quinolone class of inhibitors of bacterial type II topoisomerases has gained major clinical importance during the last years due to improvements in both pharmacokinetic and pharmacodynamic properties. These include favorable bioavailability allowing oral administration, good tolerability, high tissue concentrations as well as superior bactericidal activity against a broad spectrum of clinically relevant pathogens, like enterobacteria, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. In addition, no enzymatic mechanism of drug inactivation exists in bacteria and no indications for transfer of clinically relevant resistance exist. Nevertheless, resistance is being increasingly reported, even for naturally highly susceptible species like Escherichia coli. The underlying mechanisms of resistance include alterations in both bacterial targets, DNA gyrase and topoisomerase IV, often combined with mutations affecting drug accumulation, e.g., by increased drug efflux, reduced drug influx, or both. Investigations aiming at understanding the molecular mechanisms of quinolone action and resistance in more detail should provide a basis for a rational design of more potent derivatives. In addition, a prudent use of these highly valuable “magic bullets” is necessary to preserve their potential for the future.

Key words

Bacterial topoisomerase - fluoroquinolone - bacteria and antibiotic resistance

1 1Experimental work was performed at the Department of Pharmaceutical Microbiology at the University of Bonn

References

  • 1 Rosamond J, Allsop A. Harnessing the power of the genome in the search for new antibiotics.  Science. 2000;  287 1973-6
    CrossrefPubMedGoogle Scholar
  • 2 Wang J C. DNA topoisomerases.  Annu. Rev. Biochem.. 1996;  65 635-92
    CrossrefPubMedGoogle Scholar
  • 3 Wang J C. Interaction between DNA and an Escherichia coli protein omega.  J. Mol. Biol.. 1971;  55 523-33
    CrossrefPubMedGoogle Scholar
  • 4 Gellert M, Mizuuchi K, O'Dea M H, Nash H A. DNA gyrase: an enzyme that introduces superhelical turns into DNA.  Proc. Natl. Acad. Sci. U.S.A.. 1976;  73 3872-6
    PubMedGoogle Scholar
  • 5 Maxwell A. DNA gyrase as a drug target.  Trends. Microbiol.. 1997;  5 102-9
    CrossrefPubMedGoogle Scholar
  • 6 Reece R J, Maxwell A. DNA gyrase: structure and function.  Crit. Rev. Biochem. Mol. Biol.. 1991;  26 335-75
    PubMedGoogle Scholar
  • 7 Berger J M, Gamblin S J, Harrison S C, Wang J C. Structure and mechanism of DNA topoisomerase II.  Nature. 1996;  379 225-32
    CrossrefPubMedGoogle Scholar
  • 8 Kato J-I, Nishimura Y, Imamura Y, Niki H, Hiraga S, Suzuki H. New topoisomerase essential for chromosome segregation in E. coli .  Cell. 1990;  63 393-404
    CrossrefPubMedGoogle Scholar
  • 9 Adams D E, Shekhtman E M, Zechiedrich E L, Schmid M B, Cozzarelli N R. The role of topoisomerase IV in partitioning bacterial replicons and the structure of catenated intermediates in DNA replication.  Cell. 1992;  71 277-88
    CrossrefPubMedGoogle Scholar
  • 10 Vizan J L, Hernandez-Chico C, del Castillo I, Moreno F. The peptide antibiotic microcin B17 induces double-strand cleavage of DNA mediated by E. coli DNA gyrase.  EMBO J. 1991;  10 467-76
    PubMedGoogle Scholar
  • 11 Oram M, Dosanjh B, Gormley N A, Smith C V, Fisher L M, Maxwell A, Duncan K. Mode of action of GR122222X, a novel inhibitor of bacterial DNA gyrase.  Antimicrob. Agents Chemother.. 1996;  40 473-6
    PubMedGoogle Scholar
  • 12 Osburne M S, Maiese W M, Greenstein M. In vitro inhibition of bacterial DNA gyrase by cinodine, a glycocinnamoylspermidine antibiotic.  Antimicrob. Agents Chemother.. 1990;  34 1450-2
    PubMedGoogle Scholar
  • 13 Osburne M S. Characterization of a cinodine-resistant mutant of Escherichia coli .  J Antibiot. (Tokyo.). 1995;  48 1359-61
    PubMedGoogle Scholar
  • 14 Nakada N, Shimada H, Hirata T, Aoki Y, Kamiyama T, Watanabe J, Arisawa M. Biological characterization of cyclothialidine, a new DNA gyrase inhibitor.  Antimicrob. Agents Chemother.. 1993;  37 2656-61
    CrossrefPubMedGoogle Scholar
  • 15 Yamaji K, Masubuchi M, Kawahara F, Nakamura Y, Nishio A, Matsukuma S, Fujimori M, Nakada N, Watanabe J, Kamiyama T. Cyclothialidine analogs, novel DNA gyrase inhibitors.  J Antibiot. (Tokyo.). 1997;  50 402-11
    PubMedGoogle Scholar
  • 16 Bernard F X, Sable S, Cameron B, Provost J, Desnottes J F, Crouzet J, Blanche F. Glycosylated flavones as selective inhibitors of topoisomerase IV.  Antimicrob. Agents Chemother.. 1997;  41 992-8
    CrossrefPubMedGoogle Scholar
  • 17 Maxwell A. The interaction between coumarin drugs and DNA gyrase.  Mol. Microbiol.. 1993;  9 681-6
    PubMedGoogle Scholar
  • 18 Gellert M, O'Dea M H, Itoh T, Tomizawa J. Novobiocin and coumermycin inhibit DNA supercoiling catalyzed by DNA gyrase.  Proc. Natl. Acad. Sci. U.S.A.. 1976;  73 4474-8
    CrossrefPubMedGoogle Scholar
  • 19 Sugino A, Higgins N P, Brown P O, Peebles C L, Cozzarelli N R. Energy coupling in DNA gyrase and the mechanism of action of novobiocin.  Proc. Natl. Acad. Sci. U.S.A.. 1978;  75 4838-42
    CrossrefPubMedGoogle Scholar
  • 20 Hooper D C, Wolfson J S, McHugh G L, Winters M B, Swartz M N. Effects of novobiocin, coumermycin A1, clorobiocin, and their analogs on Escherichia coli DNA gyrase and bacterial growth.  Antimicrob. Agents Chemother.. 1982;  22 662-71
    PubMedGoogle Scholar
  • 21 Lesher G Y, Froelich E J, Gruett M D, Bailey J H, Brundage R P. 1,8-Naphthyridine derivatives, a new class of chemotherapy agents.  J. Med. Chem.. 1962;  5 1063-5
    CrossrefPubMedGoogle Scholar
  • 22 Koga H, Itoh A, Murayama S, Suzue S, Irikura T. Structure-activity relationships of antibacterial 6,7- and 7,8-disubstituted 1-alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids.  J Med. Chem.. 1980;  23 1358-63
    CrossrefPubMedGoogle Scholar
  • 23 Eliopoulos G M, Eliopoulos C T. Quinolone Antimicrobial Agents, Activity in vitro of the quinolones. In: Hooper DC, Wolfson JS, editors Washington DC; American Society for Microbiology 1993: 161-93
  • 24 Naber K G, Adam D. Expertengruppe der Paul-Ehrlich-Gesellschaft. Einteilung der Fluorchinolone.  Chemotherapie Journal. 1998;  7 66-8
    PubMedGoogle Scholar
  • 25 Bauernfeind A. Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin.  J Antimicrob. Chemother.. 1997;  40 639-51
    CrossrefPubMedGoogle Scholar
  • 26 Drlica K, Xu C, Wang J Y, Burger R M, Malik M. Fluoroquinolone action in mycobacteria: similarity with effects in Escherichia coli and detection by cell lysate viscosity.  Antimicrob. Agents Chemother.. 1996;  40 1594-9
    PubMedGoogle Scholar
  • 27 Ednie L M, Jacobs M R, Appelbaum P C. Comparative activities of clinafloxacin against Gram-positive and -negative bacteria.  Antimicrob. Agents Chemother.. 1998;  42 1269-73
    PubMedGoogle Scholar
  • 28 Felmingham D, Robbins M J, Ingley K, Mathias I, Bhogal H, Leakey A, Ridgway G L, Gruneberg R N. In-vitro activity of trovafloxacin, a new fluoroquinolone, against recent clinical isolates.  J Antimicrob. Chemother.. 1997;  39 Suppl B 43-9
    CrossrefPubMedGoogle Scholar
  • 29 Thornsberry C. Quinolone antibacterials, The in vitro antibacterial activity of quinolones: a review. In: Kuhlmann J, Dalhoff A, Zeiler H-J, editors Handbook of Experimental Pharmacology. Berlin; Springer Verlag 1998: 167-78
    Google Scholar
  • 30 Zhao X, Wang J Y, Xu C, Dong Y, Zhou J, Domagala J, Drlica K. Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones.  Antimicrob. Agents Chemother.. 1998;  42 956-8
    PubMedGoogle Scholar
  • 31 Rastogi N, Labrousse V, Goh K S, De Sousa J P. Antimycobacterial spectrum of sparfloxacin and its activities alone and in association with other drugs against Mycobacterium avium complex growing extracellularly and intracellularly in murine and human macrophages.  Antimicrob. Agents Chemother.. 1991;  35 2473-80
    PubMedGoogle Scholar
  • 32 Saito H, Tomioka H, Sato K, Dekio S. In vitro and in vivo antimycobacterial activities of a new quinolone, DU-6859a.  Antimicrob. Agents Chemother.. 1994;  38 2877-82
    PubMedGoogle Scholar
  • 33 Yew W W, Piddock L J, Li M S, Lyon D, Chan C Y, Cheng A F. In-vitro activity of quinolones and macrolides against mycobacteria.  J Antimicrob. Chemother.. 1994;  34 343-51
    PubMedGoogle Scholar
  • 34 Blondeau J M. A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new respiratory quinolones'.  J Antimicrob. Chemother.. 1999;  43 Suppl B 1-11
    PubMedGoogle Scholar
  • 35 Goss W A, Deitz W H, Cook T M. Mechanism of action of nalidixic acid on Escherichia coli (I).  J Bacteriol. 1964;  88 1112-8
    PubMedGoogle Scholar
  • 36 Goss W A, Deitz W H, Cook T M. Mechanism of action of nalidixic acid on Escherichia coli (II).  J Bacteriol. 1965;  89 1068-74
    PubMedGoogle Scholar
  • 37 Gellert M, Mizuuchi K, O'Dea M H, Itoh T, Tomizawa J I. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity.  Proc. Natl. Acad. Sci. U.S.A.. 1977;  74 4772-6
    PubMedGoogle Scholar
  • 38 Phillips I, Culebras E, Moreno F, Baquero F. Induction of the SOS response by new 4-quinolones.  J Antimicrob. Chemother.. 1987;  20 631-8
    PubMedGoogle Scholar
  • 39 Little J W, Mount D W. The SOS regulatory system of Escherichia coli .  Cell. 1982;  29 11-22
    CrossrefPubMedGoogle Scholar
  • 40 Bourguignon G J, Levitt M, Sternglanz R. Studies on the mechanism of action of nalidixic acid.  Antimicrob. Agents Chemother.. 1973;  4 379-86
    PubMedGoogle Scholar
  • 41 Martens R, Wetzstein H G, Zadrazil F, Capelari M, Hoffmann P, Schmeer N. Degradation of the fluoroquinolone enrofloxacin by wood-rotting fungi.  Appl. Environ. Microbiol.. 1996;  62 4206-9
    PubMedGoogle Scholar
  • 42 Hooper D C, Wolfson J S. Bacterial resistance to the quinolone antimicrobial agents.  Am. J. Med.. 1989;  87 17S-23S
    PubMedGoogle Scholar
  • 43 Kresken M, Hafner D. Prävalenz der Antibiotikaresistenz bei klinisch wichtigen Infeketionserregern in Mitteleuropa.  Chemotherapie Journal. 1996;  5 225-30
    PubMedGoogle Scholar
  • 44 Heisig P. Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli .  Antimicrob. Agents Chemother.. 1996;  40 879-85
    PubMedGoogle Scholar
  • 45 Lehn N, Stower-Hoffmann J, Kott T, Strassner C, Wagner H, Kronke M, Schneider-Brachert W. Characterization of clinical isolates of Escherichia coli showing high levels of fluoroquinolone resistance.  J. Clin. Microbiol.. 1996;  34 597-602
    PubMedGoogle Scholar
  • 46 Everett M J, Jin Y F, Ricci V, Piddock L J. Contributions of individual mechanisms to fluoroquinolone resistance in 36 Escherichia coli strains isolated from humans and animals.  Antimicrob. Agents Chemother.. 1996;  40 2380-6
    PubMedGoogle Scholar
  • 47 Conrad S, Oethinger M, Kaifel K, Klotz G, Marre R, Kern W V. gyrA mutations in high-level fluoroquinolone-resistant clinical isolates of Escherichia coli .  J Antimicrob. Chemother.. 1996;  38 443-55
    PubMedGoogle Scholar
  • 48 Heisig P, Tschorny R. Characterization of fluoroquinolone-resistant mutants of Escherichia coli selected in vitro .  Antimicrob. Agents Chemother.. 1994;  38 1284-91
    PubMedGoogle Scholar
  • 49 Hane M W, Wood T H. Escherichia coli K-12 mutants resistant to nalidixic acid: genetic mapping and dominance studies.  J. Bacteriol.. 1969;  99 238-41
    PubMedGoogle Scholar
  • 50 Nakamura S, Nakamura M, Kojima T, Yoshida H. gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli .  Antimicrob. Agents Chemother.. 1989;  33 254-5
    PubMedGoogle Scholar
  • 51 Heisig P, Wiedemann B. Use of a broad-host-rage gyrA plasmid for genetic characterization of fluoroquinolone-resistant gram-negative bacteria.  Antimicrob. Agents Chemother.. 1991;  35 2031-6
    PubMedGoogle Scholar
  • 52 Cohen S P, McMurry L M, Hooper D C, Wolfson J S, Levy S B. 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.. 1989;  33 1318-25
    PubMedGoogle Scholar
  • 53 Heisig P. Antibiotic Resistance - Recent Development and Future Perspectives, Mechanisms and Epidemiology of Fluoroquinolone Resistance in Enterobacteriaceae. In: Hakenbeck R, editor Biospektrum Special Edition. Heidelberg; Spektrum 1997: 42-6
    Google Scholar
  • 54 Yoshida H, Bogaki M, Nakamura M, Nakamura S. Quinolone resistance determining region in the DNA gyrase gyrA gene of Escherichia coli .  Antimicrob. Agents Chemother.. 1990;  34 1271-2
    PubMedGoogle Scholar
  • 55 Heisig P, Schedletzky H, Falkenstein-Paul H. Mutations in the gyrA gene of a highly fluoroquinolone-resistant clinical isolate of Escherichia coli .  Antimicrob. Agents Chemother.. 1993;  37 696-701
    PubMedGoogle Scholar
  • 56 Hoshino K, Kitamura A, Morrissey I, Sato K, Kato J, Ikeda H. Comparison of inhibition of Escherichia coli topoisomerase IV by quinolones with DNA gyrase inhibition.  Antimicrob. Agents Chemother.. 1994;  38 2623-7
    PubMedGoogle Scholar
  • 57 Khodursky A B, Zechiedrich E L, Cozzarelli N R. Topoisomerase IV is a target of quinolones in Escherichia coli .  Proc. Natl. Acad. Sci. U.S.A.. 1995;  92 11801-5
    PubMedGoogle Scholar
  • 58 Vila J, Ruiz J, Goni P, De Anta M T. Detection of mutations in ParC in quinolone-resistant clinical isolates of Escherichia coli .  Antimicrob. Agents Chemother.. 1996;  40 491-3
    PubMedGoogle Scholar
  • 59 Kumagai Y, Kato J I, Hoshino K, Akasaka T, Sato K, Ikeda H. Quinolone-resistant mutants of Escherichia coli DNA topoisomerase IV ParC gene.  Antimicrob. Agents Chemother.. 1996;  40 710-4
    PubMedGoogle Scholar
  • 60 Belland R J, Morrison S G, Ison C, Huang W M. Neisseria gonorrhoeae acquires mutations in analogous regions of gyrA and parC in fluoroquinolone-resistant isolates.  Mol. Microbiol.. 1994;  14 371-80
    PubMedGoogle Scholar
  • 61 Holzgrabe U, Heisig P. New 4-quinolone derivatives in review.  Pharm. Unserer. Zeit.. 1999;  28 30-5
    PubMedGoogle Scholar
  • 62 Ferrero L, Cameron B, Crouzet J. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus .  Antimicrob. Agents Chemother.. 1995;  39 1554-8
    PubMedGoogle Scholar
  • 63 Domagala J M. Structure-activity and structure-side-effect relationships for the quinolone antibacterials.  J Antimicrob. Chemother.. 1994;  33 685-706
    PubMedGoogle Scholar
  • 64 el Amin N A, Jalal S, Wretlind B. Alterations in GyrA and ParC associated with fluoroquinolone resistance in Enterococcus faecium .  Antimicrob. Agents Chemother.. 1999;  43 947-9
    PubMedGoogle Scholar
  • 65 Kanematsu E, Deguchi T, Yasuda M, Kawamura T, Nishino Y, Kawada Y. Alterations in the GyrA subunit of DNA gyrase and the ParC subunit of DNA topoisomerase IV associated with quinolone resistance in Enterococcus faecalis .  Antimcirob. Agents Chemother.. 1998;  42 433-5
    PubMedGoogle Scholar
  • 66 Pan X S, Fisher L M. Cloning and characterization of the parC and parE genes of Streptococcus pneumoniae encoding DNA topoisomerase IV: role in fluoroquinolone resistance.  J. Bacteriol.. 1996;  178 4060-9
    PubMedGoogle Scholar
  • 67 Pan X S, Fisher L M. Targeting of DNA gyrase in Streptococcus pneumoniae by sparfloxacin: selective targeting of gyrase or topoisomerase IV by quinolones.  Antimicrob. Agents Chemother.. 1997;  41 471-4
    PubMedGoogle Scholar
  • 68 Kotera Y, Watanabe M, Yoshida S, Inoue M, Mitsuhashi S. Factors influencing the uptake of norfloxacin by Escherichia coli .  J Antimicrob. Chemother.. 1991;  27 733-9
    PubMedGoogle Scholar
  • 69 Nikaido H, Thanassi D G. Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as examples.  Antimicrob. Agents Chemother.. 1993;  37 1393-9
    PubMedGoogle Scholar
  • 70 Nikaido H. Antibiotic resistance caused by Gram-negative mutlidrug efflux pumps.  Clin. Infect. Dis.. 1998;  27 Suppl 1 S32-541
    PubMedGoogle Scholar
  • 71 Chapman J S, Georgopapadakou N H. Routes of quinolone permeation in Escherichia coli .  Antimicrob. Agents Chemother.. 1988;  32 438-42
    PubMedGoogle Scholar
  • 72 Sawai T, Yamaguchi A, Saiki A, Hoshino K. OmpF channel permeability of quinolones and their comparison with beta-lactams.  FEMS Microbiol. Lett.. 1992;  74 105-8
    PubMedGoogle Scholar
  • 73 Pratt L A, Hsing W, Gibson K E, Silhavy T J. From acids to osmZ: multiple factors influence synthesis of the OmpF and OmpC porins in Escherichia coli .  Mol. Microbiol.. 1996;  20 911-7
    PubMedGoogle Scholar
  • 74 Gutmann L, Williamson R, Moreau N, Kitzis M D, Collatz E, Acar J F, Goldstein F W. Cross-resistance to nalidixic acid, trimethoprim, and chloramphenicol associated with alterations in outer membrane proteins of Klebsiella, Enterobacter, and Serratia.  J. Infect. Dis.. 1985;  151 501-7
    PubMedGoogle Scholar
  • 75 Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux.  Science. 1994;  264 382-8
    PubMedGoogle Scholar
  • 76 Chapman J S, Bertasso A, Georgopapadakou N H. Fleroxacin resistance in Escherichia coli .  Antimicrob. Agents Chemother.. 1989;  33 239-41
    PubMedGoogle Scholar
  • 77 Cohen S P, Hooper D C, Wolfson J S, Souza K S, McMurry L M, Levy S B. Endogenous active efflux of norfloxacin in susceptible Escherichia coli .  Antimicrob. Agents Chemother.. 1988;  32 1187-91
    PubMedGoogle Scholar
  • 78 Ishii H, Sato K, Hoshino K, Sato M, Yamaguchi A, Sawai T, Osada Y. Active efflux of ofloxacin by a highly quinolone-resistant strain of Proteus vulgaris .  J Antimicrob. Chemother.. 1991;  28 827-36
    PubMedGoogle Scholar
  • 79 Hagman K E, Pan W, Spratt B , Balthazar J T, Judd R C, Shafer W M. Resistance of Neisseria gonorrhoeae to antimicrobial hydrophobic agents is modulated by the mtrRCDE efflux system.  Microbiology. 1995;  141 611-22
    PubMedGoogle Scholar
  • 80 Li X Z, Nikaido H, Poole K. Role of mexA-mexB-oprM in antibiotic efflux in Pseudomonas aeruginosa .  Antimicrob. Agents Chemother.. 1995;  39 1948-53
    PubMedGoogle Scholar
  • 81 Poole K, Gotoh N, Tsujimoto H, Zhao Q, Wada A, Yamasaki T, Neshat S, Yamagishi J, Li X Z, Nishino T. Overexpression of the mexC-mexD-oprJ efflux operon in nfxB-type multidrug-resistant strains of Pseudomonas aeruginosa .  Mol. Microbiol.. 1996;  21 713-24
    CrossrefPubMedGoogle Scholar
  • 82 Fukuda H, Hosaka M, Hirai K, Iyobe S. New norfloxacin resistance gene in Pseudomonas aeruginosa PAO.  Antimicrob. Agents Chemother.. 1990;  34 1757-61
    PubMedGoogle Scholar
  • 83 Yoneyama H, Ocaktan A, Tsuda M, Nakae T. The role of mex-gene products in antibiotic extrusion in Pseudomonas aeruginosa .  Biochem. Biophys. Res. Commun.. 1997;  233 611-8
    CrossrefPubMedGoogle Scholar
  • 84 Ma D, Cook D N, Hearst J E, Nikaido H. Efflux pumps and drug resistance in Gram-negative bacteria.  Trends. Microbiol.. 1994;  2 489-93
    CrossrefPubMedGoogle Scholar
  • 85 Kern W V, Oethinger M, Jellen-Ritter A S, Levy S B. Non-target gene mutations in the development of fluoroquinolone resistance in Escherichia coli .  Antimicrob. Agents Chemother.. 2000;  44 814-20
    CrossrefPubMedGoogle Scholar
  • 86 Alekshun M N, Levy S B. Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon.  Antimicrob. Agents Chemother.. 1997;  41 2067-75
    PubMedGoogle Scholar
  • 87 Paulsen I T, Brown M H, Skurray R A. Proton-dependent multidrug efflux systems.  Microbiol. Rev.. 1996;  60 575-608
    PubMedGoogle Scholar
  • 88 Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones.  J Bacteriol. 1990;  172 6942-9
    PubMedGoogle Scholar
  • 89 Neyfakh A A, Borsch C M, Kaatz G W. Fluoroquinolone resistance protein NorA of Staphylococcus aureus is a multidrug efflux transporter.  Antimicrob. Agents Chemother.. 1993;  37 128-9
    PubMedGoogle Scholar
  • 90 Brenwald N P, Gill M J, Wise R. Prevalence of a putative efflux mechanism among fluoroquinolone-resistant clinical isolates of Streptococcus pneumoniae .  Antimicrob. Agents Chemother.. 1998;  42 2032-5
    PubMedGoogle Scholar
  • 91 Gill M J, Brenwald N P, Wise R. Identification of an efflux pump gene, pmrA, associated with fluoroquinolone resistance in Streptococcus pneumoniae .  Antimicrob. Agents Chemother.. 1999;  43 187-9
    PubMedGoogle Scholar
  • 92 Akasaka T, Onodera Y, Tanaka M, Sato K. Cloning, expression, and enzymatic characterization of Pseudomonas aeruginosa topoisomerase IV.  Antimicrob. Agents Chemother.. 1999;  43 530-6
    PubMedGoogle Scholar
  • 93 Kureishi A, Diver J M, Beckthold B, Schollaardt T, Bryan L E. Cloning and nucleotide sequence of Pseudomonas aeruginosa DNA gyrase gyrA gene from strain PAO1 and quinolone-resistant clinical isolates.  Antimicrob. Agents Chemother.. 1994;  38 1944-52
    PubMedGoogle Scholar
  • 94 Vila J, Ruiz J, Goni P, Jimenez D A. Quinolone-resistance mutations in the topoisomerase IV parC gene of Acinetobacter baumannii .  J Antimicrob. Chemother.. 1997;  39 757-62
    CrossrefPubMedGoogle Scholar
  • 95 Cohen S P, Hachler H, Levy S B. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli .  J Bacteriol. 1993;  175 1484-92
    PubMedGoogle Scholar
  • 96 Ma D, Cook D N, Alberti M, Pon N G, Nikaido H, Hearst J E. Genes acrA and acrB encode a stress-induced efflux system of Escherichia coli .  Mol. Microbiol.. 1995;  16 45-55
    PubMedGoogle Scholar
  • 97 Ma D, Alberti M, Lynch C, Nikaido H, Hearst J E. The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals.  Mol. Microbiol.. 1996;  19 101-12
    CrossrefPubMedGoogle Scholar

1 1Experimental work was performed at the Department of Pharmaceutical Microbiology at the University of Bonn

Prof. Dr. Peter Heisig

Pharmazeutische Biologie

Universität Hamburg

Bundesstraße 45

20146 Hamburg

Germany

eMail: heisig@chemie.uni-hamburg.de

Fax: +49 (0)40-42838-3895Phone: +49 (0)40-42838-3899