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Bacterial Type II Topoisomerases and Target-Mediated Drug Resistance

  • Elizabeth G. Gibson
  • Rachel E. Ashley
  • Robert J. Kerns
  • Neil Osheroff
Chapter
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)

Abstract

Fluoroquinolones are one of the most widely prescribed classes of broad-spectrum antibacterials currently in clinical use. These drugs kill bacteria by increasing DNA strand breaks generated by the type II topoisomerases, gyrase and topoisomerase IV. Despite the importance of fluoroquinolones in the treatment of bacterial infections, their usefulness is being diminished by the rise of drug resistance. The most common and clinically relevant form of fluoroquinolone resistance is target-mediated, which is caused by specific mutations in gyrase and topoisomerase IV. Although these mutations were first identified over 30 years ago, the mechanism by which they cause resistance has only recently been established. This knowledge has contributed greatly to our understanding of how fluoroquinolones interact with their enzyme targets and has suggested mechanisms for overcoming resistance. In order to more fully describe target-mediated fluoroquinolone resistance, this article will provide background on the drug class, discuss how gyrase and topoisomerase IV function, describe the basis for fluoroquinolone-enzyme interactions, and discuss how altering these interactions leads to resistance. Finally, new approaches to overcoming target-mediated fluoroquinolone resistance will be discussed.

Notes

Acknowledgments

The authors of this article were supported by the US Veterans Administration (Merit Review Award I01 Bx002198 to N.O.), the National Institutes of Health (grants AI87671 to R.J.K., GM33944 and GM126363 to N.O., and GM007628 to E.G.G.), the National Science Foundation (grant DGE-0909667 to R.E.A.), the Pharmaceutical Research and Manufacturers of America Foundation (to E.G.G.), and the American Association of Pharmaceutical Scientists Foundation (to E.G.G.).

References

  1. 1.
    Andriole VT. The quinolones: past, present, and future. Clin Infect Dis. 2005;41(Suppl. 2):S113–9.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Drlica K, Hiasa H, Kerns R, Malik M, Mustaev A, Zhao X. Quinolones: action and resistance updated. Curr Top Med Chem. 2009;9(11):981–98.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Hooper DC. Mechanisms of action of antimicrobials: focus on fluoroquinolones. Clin Infect Dis. 2001;32(Suppl. 1):S9–S15.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Linder JA, Huang ES, Steinman MA, Gonzales R, Stafford RS. Fluoroquinolone prescribing in the United States: 1995 to 2002. Am J Med. 2005;118(3):259–68.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Hooper DC. Clinical applications of quinolones. Biochim Biophys Acta. 1998;1400:45–61.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Ressel G. Centers for Disease Control and Prevention. CDC updates interim guidelines for anthrax exposure management and antimicrobial therapy. Am Fam Physician. 2001;64(11):1901–2. 4PubMedPubMedCentralGoogle Scholar
  7. 7.
    Jeon D. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update: applicability in South Korea. Tuberc Respir Dis (Seoul). 2017;80(4):336–43.CrossRefGoogle Scholar
  8. 8.
    WHO. Global tuberculosis report 2016. 2016.Google Scholar
  9. 9.
    Anderson VE, Osheroff N. Type II topoisomerases as targets for quinolone antibacterials: turning Dr. Jekyll into Mr. Hyde. Curr Pharm Des. 2001;7(5):337–53.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369–413.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Aldred KJ, Kerns RJ, Osheroff N. Mechanism of quinolone action and resistance. Biochemistry. 2014;53(10):1565–74.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bush NG, Evans-Roberts K, Maxwell A. DNA topoisomerases. EcoSal Plus. 2015;6(2)Google Scholar
  13. 13.
    Levine C, Hiasa H, Marians KJ. DNA gyrase and topoisomerase IV: biochemical activities, physiological roles during chromosome replication, and drug sensitivities. Biochim Biophys Acta. 1998;1400:29–43.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Deweese JE, Burch AM, Burgin AB, Osheroff N. Use of divalent metal ions in the DNA cleavage reaction of human type II topoisomerases. Biochemistry. 2009;48(9):1862–9.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Gentry AC. DNA topoisomerases: type II. In: Lennarz WJ, Daniel Lane M, editors. The encyclopedia of biological chemistry. Waltham: Academic; 2013. p. 163–8.CrossRefGoogle Scholar
  16. 16.
    Fraser CM, Norris SJ, Weinstock GM, White O, Sutton GG, Dodson R, et al. Complete genome sequence of Treponema pallidum, the syphilis spirochete. Science. 1998;281(5375):375–88.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, et al. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 1997;388(6642):539–47.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Parkhill J, Wren BW, Mungall K, Ketley JM, Churcher C, Basham D, et al. The genome sequence of the food-borne pathogen Campylobacter jejuni reveals hypervariable sequences. Nature. 2000;403(6770):665–8.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Cole ST, Eiglmeier K, Parkhill J, James KD, Thomson NR, Wheeler PR, et al. Massive gene decay in the leprosy bacillus. Nature. 2001;409(6823):1007–11.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Cole ST, Barrell BG. Analysis of the genome of Mycobacterium tuberculosis H37Rv. Novartis Found Symp. 1998;217:160–72. discussion 72–7PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Ashley RE, Blower TR, Berger JM, Osheroff N. Recognition of DNA supercoil geometry by Mycobacterium tuberculosis gyrase. Biochemistry. 2017;56:5440.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Aldred KJ, Schwanz HA, Li G, McPherson SA, Turnbough CL, Kerns RJ, et al. Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug–enzyme interactions. ACS Chem Biol. 2013;8(12):2660–8.PubMedCrossRefGoogle Scholar
  23. 23.
    Wohlkonig A, Chan PF, Fosberry AP, Homes P, Huang J, Kranz M, et al. Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. Nat Struct Mol Biol. 2010;17(9):1152–3.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Lesher GY, Froelich EJ, Gruett MD, Bailey JH, Brundage RP. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Pharm Chem. 1962;91:1063–5.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Emmerson AM, Jones AM. The quinolones: decades of development and use. J Antimicrob Chemother. 2003;51(Suppl 1):13–20.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Mitscher LA. Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents. Chem Rev. 2005;105(2):559–92.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Stein GE. The 4-quinolone antibiotics: past, present, and future. Pharmacotherapy. 1988;8(6):301–14.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Drusano G, Labro MT, Cars O, Mendes P, Shah P, Sorgel F, et al. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Clin Microbiol Infect. 1998;4(Suppl 2):S27–41.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Nitiss JL. Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer. 2009;9(5):338–50.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Deweese JE, Osheroff MA, Osheroff N. DNA topology and topoisomerases: teaching a “knotty” subject. Biochem Mol Biol Educ. 2008;37(1):2–10.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Vos SM, Tretter EM, Schmidt BH, Berger JM. All tangled up: how cells direct, manage and exploit topoisomerase function. Nat Rev Mol Cell Biol. 2011;12(12):827–41.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002;3(6):430–40.PubMedCrossRefGoogle Scholar
  33. 33.
    Liu Z, Deibler RW, Chan HS, Zechiedrich L. The why and how of DNA unlinking. Nucleic Acids Res. 2009;37(3):661–71.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Deweese JE, Osheroff N. The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res. 2009;37(3):738–48.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chem Biol. 2010;17(5):421–33.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Gellert M, Mizuuchi K, O'Dea MH, Nash HA. DNA gyrase: an enzyme that introduces superhelical turns into DNA. Proc Natl Acad Sci U S A. 1976;73:3872–6.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Bates AD, Berger JM, Maxwell A. The ancestral role of ATP hydrolysis in type II topoisomerases: prevention of DNA double-strand breaks. Nucleic Acids Res. 2011;39(15):6327–39.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Gentry AC, Osheroff N. DNA topoisomerases: type II. In:Encyclopedia of biological chemistry. Amsterdam: Elsevier Inc.; 2013. p. 163–8.CrossRefGoogle Scholar
  39. 39.
    Corbett KD, Berger JM. Structure, molecular mechanisms, and evolutionary relationships in DNA topoisomerases. Annu Rev Biophys Biomol Struct. 2004;33:95–118.PubMedCrossRefGoogle Scholar
  40. 40.
    Hiasa H, Marians KJ. Topoisomerase IV can support oriC DNA replication in vitro. J Biol Chem. 1994;269(23):16371–5.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Zechiedrich EL, Khodursky AB, Bachellier S, Schneider R, Chen D, Lilley DM, et al. Roles of topoisomerases in maintaining steady-state DNA supercoiling in Escherichia coli. J Biol Chem. 2000;275(11):8103–13.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Crisona NJ, Strick TR, Bensimon D, Croquette V, Cozzarelli NR. Preferential relaxation of positively supercoiled DNA by E. coli topoisomerase IV in single-molecule and ensemble measurements. Genes Dev. 2000;14(22):2881–92.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Wang X, Reyes-Lamothe R, Sherratt DJ. Modulation of Escherichia coli sister chromosome cohesion by topoisomerase IV. Genes Dev. 2008;22(17):2426–33.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Joshi MC, Magnan D, Montminy TP, Lies M, Stepankiw N, Bates D. Regulation of sister chromosome cohesion by the replication fork tracking protein SeqA. PLoS Genet. 2013;9(8):e1003673.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zawadzki P, Stracy M, Ginda K, Zawadzka K, Lesterlin C, Kapanidis AN, et al. The localization and action of topoisomerase IV in Escherichia coli chromosome segregation is coordinated by the SMC complex, MukBEF. Cell Rep. 2015;13(11):2587–96.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Pendleton M, Lindsey RH Jr, Felix CA, Grimwade D, Osheroff N. Topoisomerase II and leukemia. Ann N Y Acad Sci. 2014;1310:98–110.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Liu LF, Wang JC. DNA-DNA gyrase complex: the wrapping of the DNA duplex outside the enzyme. Cell. 1978;15(3):979–84.PubMedCrossRefGoogle Scholar
  48. 48.
    Kampranis SC, Maxwell A. Conversion of DNA gyrase into a conventional type II topoisomerase. Proc Natl Acad Sci U S A. 1996;93(25):14416–21.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Kramlinger VM, Hiasa H. The “GyrA-box” is required for the ability of DNA gyrase to wrap DNA and catalyze the supercoiling reaction. J Biol Chem. 2006;281(6):3738–42.PubMedCrossRefGoogle Scholar
  50. 50.
    Ullsperger C, Cozzarelli NR. Contrasting enzymatic acitivites of topoisomerase IV and DNA gyrase from Escherichia coli. J Biol Chem. 1996;271:31549–55.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Marians KJ. DNA gyrase-catalyzed decatenation of multiply linked DNA dimers. J Biol Chem. 1987;262(21):10362–8.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Brown PO, Cozzarelli NR. A sign inversion mechanism for enzymatic supercoiling of DNA. Science. 1979;206(4422):1081–3.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Drlica K, Snyder M. Superhelical Escherichia coli DNA: relaxation by coumermycin. J Mol Biol. 1978;120(2):145–54.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Koster DA, Crut A, Shuman S, Bjornsti MA, Dekker NH. Cellular strategies for regulating DNA supercoiling: a single-molecule perspective. Cell. 2010;142(4):519–30.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Pruss GJ, Manes SH, Drlica K. Escherichia coli DNA topoisomerase I mutants: increased supercoiling is corrected by mutations near gyrase genes. Cell. 1982;31(1):35–42.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Menzel R, Gellert M. Regulation of the genes for E. coli DNA gyrase: homeostatic control of DNA supercoiling. Cell. 1983;34(1):105–13.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Drlica K, Malik M, Kerns RJ, Zhao X. Quinolone-mediated bacterial death. Antimicrob Agents Chemother. 2008;52(2):385–92.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Hooper DC. Mechanisms of fluoroquinolone resistance. Drug Resist Updat. 1999;2(1):38–55.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Kreuzer KN, Cozzarelli NR. Escherichia coli mutants thermosensitive for deoxyribonucleic acid gyrase subunit A: effects on deoxyribonucleic acid replication, transcription, and bacteriophage growth. J Bacteriol. 1979;140(2):424–35.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, et al. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature. 2010;466(7309):935–40.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Laponogov I, Pan XS, Veselkov DA, McAuley KE, Fisher LM, Sanderson MR. Structural basis of gate-DNA breakage and resealing by type II topoisomerases. PLoS One. 2010;5(6):e11338.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Laponogov I, Sohi MK, Veselkov DA, Pan XS, Sawhney R, Thompson AW, et al. Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases. Nat Struct Mol Biol. 2009;16(6):667–9.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Aldred KJ, Blower TR, Kerns RJ, Berger JM, Osheroff N. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: enhancing drug activity against wild-type and resistant gyrase. Proc Natl Acad Sci U S A. 2016;113(7):E839–46.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Blower TR, Williamson BH, Kerns RJ, Berger JM. Crystal structure and stability of gyrase-fluoroquinolone cleaved complexes from Mycobacterium tuberculosis. Proc Natl Acad Sci U S A. 2016;113(7):1706–13.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Aldred KJ, Breland EJ, Vlčková V, Strub MP, Neuman KC, Kerns RJ, et al. Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV. Biochemistry. 2014;53(34):5558–67.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Collignon PC, Conly JM, Andremont A, McEwen SA, Aidara-Kane A, World Health Organization Advisory Group BMoISoAR, et al. World Health Organization ranking of antimicrobials according to their importance in human medicine: a critical step for developing risk management strategies to control antimicrobial resistance from food animal production. Clin Infect Dis. 2016;63(8):1087–93.PubMedCrossRefGoogle Scholar
  67. 67.
    CDC. Antibiotic/antimicrobial resistance. 2017. Available from: https://www.cdc.gov/drugresistance/biggest_threats.html.
  68. 68.
    Koebler J. World Health Organization warns gonorrhea could join HIV as ‘uncurable’. US News and World Reports. 2012 June 6.Google Scholar
  69. 69.
    CDC. 2015 Sexually transmitted diseases surveillance. 2015. Available from: https://www.cdc.gov/std/stats15/toc.htm.
  70. 70.
    Peterman TA, O'Connor K, Bradley HM, Torrone EA, Bernstein KT. Gonorrhea control, United States, 1972-2015, a narrative review. Sex Transm Dis. 2016;43(12):725–30.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Morgan MK, Decker CF. Gonorrhea. Dis Mon. 2016;62(8):260–8.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Kirkcaldy RD, Harvey A, Papp JR, Del Rio C, Soge OO, Holmes KK, et al. Neisseria gonorrhoeae antimicrobial susceptibility surveillance – the Gonococcal Isolate Surveillance Project, 27 sites, United States, 2014. MMWR Surveill Summ. 2016;65(7):1–19.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Chen PL, Lee HC, Yan JJ, Hsieh YH, Lee NY, Ko NY, et al. High prevalence of mutations in quinolone-resistance-determining regions and mtrR loci in polyclonal Neisseria gonorrhoeae isolates at a tertiary hospital in Southern Taiwan. J Formos Med Assoc. 2010;109(2):120–7.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    WHO. Global priority list of antibioitic-resistant bacteria to guide research, discovery, and development of new antibiotics. 2017.Google Scholar
  75. 75.
    Aldred KJ, McPherson SA, Wang P, Kerns RJ, Graves DE, Turnbough CL Jr, et al. Drug interactions with Bacillus anthracis topoisomerase IV: biochemical basis for quinolone action and resistance. Biochemistry. 2012;51(1):370–81.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Pan XS, Gould KA, Fisher LM. Probing the differential interactions of quinazolinedione PD 0305970 and quinolones with gyrase and topoisomerase IV. Antimicrob Agents Chemother. 2009;53(9):3822–31.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Hiasa H. The Glu-84 of the ParC subunit plays critical roles in both topoisomerase IV-quinolone and topoisomerase IV-DNA interactions. Biochemistry. 2002;41(39):11779–85.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Robicsek A, Jacoby GA, Hooper DC. The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect Dis. 2006;6(10):629–40.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Tran JH, Jacoby GA. Mechanism of plasmid-mediated quinolone resistance. Proc Natl Acad Sci U S A. 2002;99(8):5638–42.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Tsai YK, Liou CH, Chang FY, Fung CP, Lin JC, Siu LK. Effects of different resistance mechanisms on susceptibility to different classes of antibiotics in Klebsiella pneumoniae strains: a strategic system for the screening and activity testing of new antibiotics. J Antimicrob Chemother. 2017;72:3302.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Munita JM, Arias CA. Mechanisms of antibiotic resistance. Microbiol Spectr. 2016;4(2)Google Scholar
  82. 82.
    Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010;74(3):417–33.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Morgan-Linnell SK, Becnel Boyd L, Steffen D, Zechiedrich L. Mechanisms accounting for fluoroquinolone resistance in Escherichia coli clinical isolates. Antimicrob Agents Chemother. 2009;53(1):235–41.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Price LB, Vogler A, Pearson T, Busch JD, Schupp JM, Keim P. In vitro selection and characterization of Bacillus anthracis mutants with high-level resistance to ciprofloxacin. Antimicrob Agents Chemother. 2003;47(7):2362–5.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Malik M, Mustaev A, Schwanz HA, Luan G, Shah N, Oppegard LM, et al. Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones. Nucleic Acids Res. 2016;44(7):3304–16.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Strahilevitz J, Robicsek A, Hooper DC. Role of the extended alpha4 domain of Staphylococcus aureus gyrase a protein in determining low sensitivity to quinolones. Antimicrob Agents Chemother. 2006;50(2):600–6.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Malik M, Marks KR, Mustaev A, Zhao X, Chavda K, Kerns RJ, et al. Fluoroquinolone and quinazolinedione activities against wild-type and gyrase mutant strains of Mycobacterium smegmatis. Antimicrob Agents Chemother. 2011;55(5):2335–43.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Pfeiffer ES, Hiasa H. Replacement of ParC alpha4 helix with that of GyrA increases the stability and cytotoxicity of topoisomerase IV-quinolone-DNA ternary complexes. Antimicrob Agents Chemother. 2004;48(2):608–11.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Hiramatsu K, Igarashi M, Morimoto Y, Baba T, Umekita M, Akamatsu Y. Curing bacteria of antibiotic resistance: reverse antibiotics, a novel class of antibiotics in nature. Int J Antimicrob Agents. 2012;39(6):478–85.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Aldred KJ, McPherson SA, Turnbough CL Jr, Kerns RJ, Osheroff N. Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: mechanistic basis of quinolone resistance. Nucleic Acids Res. 2013;41(8):4628–39.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Sugino A, Peebles CL, Kreuzer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc Natl Acad Sci U S A. 1977;74(11):4767–71.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Gellert M, Mizuuchi K, O'Dea MH, Itoh T, Tomizawa J. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci U S A. 1977;74:4772–6.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Khodursky AB, Zechiedrich EL, Cozzarelli NR. Topoisomerase IV is a target of quinolones in Escherichia coli. Proc Natl Acad Sci U S A. 1995;92:11801–5.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Pan X-S, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1996;40(10):2321–6.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Fournier B, Zhao X, Lu T, Drlica K, Hooper DC. Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: different patterns of quinolone-induced inhibition of DNA synthesis. Antimicrob Agents Chemother. 2000;44(8):2160–5.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Pan X-S, Fisher LM. DNA gyrase and topoisomerase IV are dual targets of clinafloxacin action in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1998;42:2810–6.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Aldred KJ, Breland EJ, McPherson SA, Turnbough CL Jr, Kerns RJ, Osheroff N. Bacillus anthracis GrlAV96A topoisomerase IV, a quinolone resistance mutation that does not affect the water-metal ion bridge. Antimicrob Agents Chemother. 2014;58(12):7182–7.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Ashley RE, Lindsey RH Jr, McPherson SA, Turnbough CL Jr, Kerns RJ, Osheroff N. Interactions between quinolones and Bacillus anthracis gyrase and the basis of drug resistance. Biochemistry. 2017;56(32):4191–200.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Cullen ME, Wyke AW, Kuroda R, Fisher LM. Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones. Antimicrob Agents Chemother. 1989;33(6):886–94.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Sreedharan S, Oram M, Jensen B, Peterson LR, Fisher LM. DNA gyrase gyrA mutations in ciprofloxacin-resistant strains of Staphylococcus aureus: close similarity with quinolone resistance mutations in Escherichia coli. J Bacteriol. 1990;172(12):7260–2.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Hopewell R, Oram M, Briesewitz R, Fisher LM. DNA cloning and organization of the Staphylococcus aureus gyrA and gyrB genes: close homology among gyrase proteins and implications for 4-quinolone action and resistance. J Bacteriol. 1990;172(6):3481–4.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Oram M, Fisher LM. 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother. 1991;35(2):387–9.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Aldred KJ, Schwanz HA, Li G, Williamson BH, McPherson SA, Turnbough CL Jr, et al. Activity of quinolone CP-115,955 against bacterial and human type II topoisomerases is mediated by different interactions. Biochemistry. 2015;54(5):1278–86.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Drlica K, Mustaev A, Towle TR, Luan G, Kerns RJ, Berger JM. Bypassing fluoroquinolone resistance with quinazolinediones: studies of drug-gyrase-DNA complexes having implications for drug design. ACS Chem Biol. 2014;9(12):2895–904.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Elsea SH, McGuirk PR, Gootz TD, Moynihan M, Osheroff N. Drug features that contribute to the activity of quinolones against mammalian topoisomerase II and cultured cells: correlation between enhancement of enzyme-mediated DNA cleavage in vitro and cytotoxic potential. Antimicrob Agents Chemother. 1993;37(10):2179–86.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Elsea SH, Osheroff N, Nitiss JL. Cytotoxicity of quinolones toward eukaryotic cells. Identification of topoisomerase II as the primary cellular target for the quinolone CP-115,953 in yeast. J Biol Chem. 1992;267(19):13150–3.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Coates WJ, et al. Preparation of piperidinylalkylquinolines as antibacterials. 1999; United States Patent W09937635.Google Scholar
  108. 108.
    Gomez L, Hack MD, Wu J, Wiener JJ, Venkatesan H, Santillan A Jr, et al. Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: synthesis and preliminary SAR analysis. Bioorg Med Chem Lett. 2007;17(10):2723–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Black MT, Stachyra T, Platel D, Girard AM, Claudon M, Bruneau JM, et al. Mechanism of action of the antibiotic NXL101, a novel nonfluoroquinolone inhibitor of bacterial type II topoisomerases. Antimicrob Agents Chemother. 2008;52(9):3339–49.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Negash K, Andonian C, Felgate C, Chen C, Goljer I, Squillaci B, et al. The metabolism and disposition of GSK2140944 in healthy human subjects. Xenobiotica. 2016;46(8):683–702.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Blanco D, Perez-Herran E, Cacho M, Ballell L, Castro J, Gonzalez Del Rio R, et al. Mycobacterium tuberculosis gyrase inhibitors as a new class of antitubercular drugs. Antimicrob Agents Chemother. 2015;59(4):1868–75.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Kern G, Palmer T, Ehmann DE, Shapiro AB, Andrews B, Basarab GS, et al. Inhibition of Neisseria gonorrhoeae Type II Topoisomerases by the Novel Spiropyrimidinetrione AZD0914. J Biol Chem. 2015;290(34):20984–94.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Huband MD, Bradford PA, Otterson LG, Basarab GS, Kutschke AC, Giacobbe RA, et al. In vitro antibacterial activity of AZD0914, a new spiropyrimidinetrione DNA gyrase/topoisomerase inhibitor with potent activity against gram-positive, fastidious gram-negative, and atypical bacteria. Antimicrob Agents Chemother. 2015;59(1):467–74.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Giacobbe RA, Huband MD, de Jonge BL, Bradford PA. Effect of susceptibility testing conditions on the in vitro antibacterial activity of ETX0914. Diagn Microbiol Infect Dis. 2017;87(2):139–42.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Elizabeth G. Gibson
    • 1
  • Rachel E. Ashley
    • 2
  • Robert J. Kerns
    • 3
  • Neil Osheroff
    • 4
  1. 1.Department of PharmacologyVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of BiochemistryVanderbilt University School of MedicineNashvilleUSA
  3. 3.Department of Pharmaceutical Sciences and Experimental TherapeuticsUniversity of Iowa College of PharmacyIowa CityUSA
  4. 4.Departments of Biochemistry and Medicine, VA Tennessee Valley Healthcare SystemVanderbilt University School of MedicineNashvilleUSA

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