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

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
• 2 Wang J C. DNA topoisomerases.  Annu. Rev. Biochem.. 1996;  65 635-92
• 3 Wang J C. Interaction between DNA and an Escherichia coli protein omega.  J. Mol. Biol.. 1971;  55 523-33
• 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
• 5 Maxwell A. DNA gyrase as a drug target.  Trends. Microbiol.. 1997;  5 102-9
• 6 Reece R J, Maxwell A. DNA gyrase: structure and function.  Crit. Rev. Biochem. Mol. Biol.. 1991;  26 335-75
• 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
• 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
• 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
• 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
• 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
• 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
• 13 Osburne M S. Characterization of a cinodine-resistant mutant of Escherichia coli .  J Antibiot. (Tokyo.). 1995;  48 1359-61
• 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
• 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
• 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
• 17 Maxwell A. The interaction between coumarin drugs and DNA gyrase.  Mol. Microbiol.. 1993;  9 681-6
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 39 Little J W, Mount D W. The SOS regulatory system of Escherichia coli .  Cell. 1982;  29 11-22
• 40 Bourguignon G J, Levitt M, Sternglanz R. Studies on the mechanism of action of nalidixic acid.  Antimicrob. Agents Chemother.. 1973;  4 379-86
• 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
• 42 Hooper D C, Wolfson J S. Bacterial resistance to the quinolone antimicrobial agents.  Am. J. Med.. 1989;  87 17S-23S
• 43 Kresken M, Hafner D. Prävalenz der Antibiotikaresistenz bei klinisch wichtigen Infeketionserregern in Mitteleuropa.  Chemotherapie Journal. 1996;  5 225-30
• 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
• 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
• 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
• 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
• 48 Heisig P, Tschorny R. Characterization of fluoroquinolone-resistant mutants of Escherichia coli selected in vitro .  Antimicrob. Agents Chemother.. 1994;  38 1284-91
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 61 Holzgrabe U, Heisig P. New 4-quinolone derivatives in review.  Pharm. Unserer. Zeit.. 1999;  28 30-5
• 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
• 63 Domagala J M. Structure-activity and structure-side-effect relationships for the quinolone antibacterials.  J Antimicrob. Chemother.. 1994;  33 685-706
• 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
• 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
• 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
• 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
• 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
• 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
• 70 Nikaido H. Antibiotic resistance caused by Gram-negative mutlidrug efflux pumps.  Clin. Infect. Dis.. 1998;  27 Suppl 1 S32-541
• 71 Chapman J S, Georgopapadakou N H. Routes of quinolone permeation in Escherichia coli .  Antimicrob. Agents Chemother.. 1988;  32 438-42
• 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
• 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
• 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
• 75 Nikaido H. Prevention of drug access to bacterial targets: permeability barriers and active efflux.  Science. 1994;  264 382-8
• 76 Chapman J S, Bertasso A, Georgopapadakou N H. Fleroxacin resistance in Escherichia coli .  Antimicrob. Agents Chemother.. 1989;  33 239-41
• 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
• 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
• 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
• 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
• 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
• 82 Fukuda H, Hosaka M, Hirai K, Iyobe S. New norfloxacin resistance gene in Pseudomonas aeruginosa PAO.  Antimicrob. Agents Chemother.. 1990;  34 1757-61
• 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
• 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
• 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
• 86 Alekshun M N, Levy S B. Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon.  Antimicrob. Agents Chemother.. 1997;  41 2067-75
• 87 Paulsen I T, Brown M H, Skurray R A. Proton-dependent multidrug efflux systems.  Microbiol. Rev.. 1996;  60 575-608
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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

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