Non-quinolone Topoisomerase Inhibitors

  • Anthony MaxwellEmail author
  • Natassja G. Bush
  • Thomas Germe
  • Shannon J. McKie
Part of the Emerging Infectious Diseases of the 21st Century book series (EIDC)


Fluoroquinolone antibiotics, such as ciprofloxacin, levofloxacin, and moxifloxacin, have enjoyed enormous success over the past few decades. However, resistance to these compounds is rising and causing significant concern. These drugs target the type II DNA topoisomerases, DNA gyrase, and DNA topoisomerase (topo) IV. A key feature of their success is that they cause enzyme-stabilized double-stranded breaks in DNA, which can readily lead to bacterial cell death. There are, however, many other compounds that target gyrase and topo IV both via the cleavage-complex mode of action and via other modes of inhibition, such as blocking the ATPase activity of these enzymes. The purpose of this chapter is to review our knowledge of these compounds and to discuss the possibility that one or more of these compounds will become clinically-relevant, perhaps by replacing the fluoroquinolones. Compounds covered include well-established agents, such as the aminocoumarins, which predate the quinolones in terms of their discovery, and a variety of more recently-discovered compounds whose clinical potential has yet to be fully explored.


  1. 1.
    Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB, et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1–12.PubMedCrossRefGoogle Scholar
  2. 2.
    Bush K, Courvalin P, Dantas G, Davies J, Eisenstein B, Huovinen P, et al. Tackling antibiotic resistance. Nat Rev Microbiol. 2011;9(12):894–6.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Lewis K. Antibiotics: Recover the lost art of drug discovery. Nature. 2012;485(7399):439–40.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Walsh CT, Wencewicz TA. Prospects for new antibiotics: a molecule-centered perspective. J Antibiot (Tokyo). 2014;67(1):7–22.CrossRefGoogle Scholar
  5. 5.
    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
  6. 6.
    Pitiriga V, Vrioni G, Saroglou G, Tsakris A. The impact of antibiotic stewardship programs in combating quinolone resistance: a systematic review and recommendations for more efficient interventions. Adv Ther. 2017;34(4):854–65.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Hooper DC. Mechanisms of quinolone resistance. In: Hooper DC, Rubinstein E, editors. Quinolone antimicrobial agents. 3rd ed. Washington, DC: ASM Press; 2003. p. 41–67.Google Scholar
  8. 8.
    Redgrave LS, Sutton SB, Webber MA, Piddock LJ. Fluoroquinolone resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends Microbiol. 2014;22(8):438–45.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    WHO. Critically important antimicrobials for human medicine – 5 rev. June 2017 Ed. Geneva: World Health Organisation – WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (AGISAR); 2017.Google Scholar
  10. 10.
    Bush NG, Evans-Roberts K, Maxwell A. DNA topoisomerases. EcoSal Plus. 2015;6(2).Google Scholar
  11. 11.
    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
  12. 12.
    Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002;3(6):430–40.PubMedCrossRefGoogle Scholar
  13. 13.
    Forterre P, Gribaldo S, Gadelle D, Serre MC. Origin and evolution of DNA topoisomerases. Biochimie. 2007;89(4):427–46.PubMedCrossRefGoogle Scholar
  14. 14.
    Wang JC. DNA topoisomerases. Annu Rev Biochem. 1996;65:635–92.PubMedCrossRefGoogle Scholar
  15. 15.
    Gadelle D, Filee J, Buhler C, Forterre P. Phylogenomics of type II DNA topoisomerases. BioEssays. 2003;25(3):232–42.PubMedCrossRefGoogle Scholar
  16. 16.
    Aravind L, Iyer LM, Wellems TE, Miller LH. Plasmodium biology: genomic gleanings. Cell. 2003;115(7):771–85.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Sugimoto-Shirasu K, Stacey NJ, Corsar J, Roberts K, McCann MC. DNA topoisomerase VI is essential for endoreduplication in Arabidopsis. Curr Biol. 2002;12(20):1782–6.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Wang JC. Moving one DNA double helix through another by a type II DNA topoisomerase: the story of a simple molecular machine. Q Rev Biophys. 1998;31(2):107–44.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Mayer C, Janin YL. Non-quinolone inhibitors of bacterial type IIA topoisomerases: a feat of bioisosterism. Chem Rev. 2014;114(4):2313–42.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Nagaraja V, Godbole AA, Henderson SR, Maxwell A. DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov Today. 2017;22(3):510–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Collin F, Karkare S, Maxwell A. Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Appl Microbiol Biotechnol. 2011;92(3):479–97.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Pommier P, Capranico G, Orr A, Kohn KW. Distribution of topoisomerase II cleavage sites in simian virus 40 DNA and the effects of drugs. J Mol Biol. 1991;222:909–24.PubMedCrossRefGoogle Scholar
  23. 23.
    De Souza MV. New fluoroquinolones: a class of potent antibiotics. Mini Rev Med Chem. 2005;5(11):1009–17.PubMedCrossRefGoogle Scholar
  24. 24.
    Oliphant CM, Green GM. Quinolones: a comprehensive review. Am Fam Physician. 2002;65(3):455–64.PubMedGoogle Scholar
  25. 25.
    Tse-Dinh YC. Bacterial topoisomerase I as a target for discovery of antibacterial compounds. Nucleic Acids Res. 2009;37(3):731–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Sandhaus S, Annamalai T, Welmaker G, Houghten RA, Paz C, Garcia PK, et al. Small-molecule inhibitors targeting topoisomerase I as novel antituberculosis agents. Antimicrob Agents Chemother. 2016;60(7):4028–36.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Cheng B, Cao S, Vasquez V, Annamalai T, Tamayo-Castillo G, Clardy J, et al. Identification of anziaic acid, a lichen depside from Hypotrachyna sp., as a new topoisomerase poison inhibitor. PLoS One. 2013;8(4):e60770.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Aldred KJ, Kerns RJ, Osheroff N. Mechanism of quinolone action and resistance. Biochemistry. 2014;53(10):1565–74.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    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
  30. 30.
    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
  31. 31.
    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
  32. 32.
    Laponogov I, Sohi MK, Veselkov DA, Pan X-S, 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
  33. 33.
    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
  34. 34.
    Ellsworth EL, Tran TP, Showalter HD, Sanchez JP, Watson BM, Stier MA, et al. 3-aminoquinazolinediones as a new class of antibacterial agents demonstrating excellent antibacterial activity against wild-type and multidrug resistant organisms. J Med Chem. 2006;49(22):6435–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Huband MD, Cohen MA, Zurack M, Hanna DL, Skerlos LA, Sulavik MC, et al. In vitro and in vivo activities of PD 0305970 and PD 0326448, new bacterial gyrase/topoisomerase inhibitors with potent antibacterial activities versus multidrug-resistant gram-positive and fastidious organism groups. Antimicrob Agents Chemother. 2007;51(4):1191–201.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Tran TP, Ellsworth EL, Sanchez JP, Watson BM, Stier MA, Showalter HD, et al. Structure-activity relationships of 3-aminoquinazolinediones, a new class of bacterial type-2 topoisomerase (DNA gyrase and topo IV) inhibitors. Bioorg Med Chem Lett. 2007;17(5):1312–20.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Germe T, Voros J, Jeannot F, Tailler T, Stavenger RA, Bacqué E, et al. A new class of antibacterials, the imidizopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Nucleic Acids Res. (in press).Google Scholar
  38. 38.
    Jeannot F, Taillier T, Despeyroux P, Renard S, Rey A, Mourez M, et al. Imidazopyrazinones (IPYs): novel non-quinolone bacterial topoisomerase inhibitors showing partial cross-resistance with quinolones. (in press).Google Scholar
  39. 39.
    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
  40. 40.
    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
  41. 41.
    Aldred KJ, Schwanz HA, Li G, McPherson SA, Turnbough CL Jr, 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
  42. 42.
    German N, Malik M, Rosen JD, Drlica K, Kerns RJ. Use of gyrase resistance mutants to guide selection of 8-methoxy-quinazoline-2,4-diones. Antimicrob Agents Chemother. 2008;52(11):3915–21.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Oppegard LM, Streck KR, Rosen JD, Schwanz HA, Drlica K, Kerns RJ, et al. Comparison of in vitro activities of fluoroquinolone-like 2,4- and 1,3-diones. Antimicrob Agents Chemother. 2010;54(7):3011–4.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Mustaev A, Malik M, Zhao X, Kurepina N, Luan G, Oppegard LM, et al. Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding. J Biol Chem. 2014.Google Scholar
  45. 45.
    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
  46. 46.
    Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, et al. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Nat Commun. 2015;6:10048.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Biedenbach DJ, Bouchillon SK, Hackel M, Miller LA, Scangarella-Oman NE, Jakielaszek C, et al. In vitro activity of gepotidacin, a novel triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of bacterial pathogens. Antimicrob Agents Chemother. 2016;60(3):1918–23.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Chan PF, Germe T, Bax BD, Huang J, Thalji RK, Bacque E, et al. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Proc Natl Acad Sci U S A. 2017;114(22):E4492–E500.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    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
  50. 50.
    Parks WM, Bottrill AR, Pierrat OA, Durrant MC, Maxwell A. The action of the bacterial toxin, microcin B17, on DNA gyrase. Biochimie. 2007;89:500–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Heddle JG, Blance SJ, Zamble DB, Hollfelder F, Miller DA, Wentzell LM, et al. The antibiotic microcin B17 is a DNA gyrase poison: characterisation of the mode of inhibition. J Mol Biol. 2001;307(5):1223–34.PubMedCrossRefGoogle Scholar
  52. 52.
    Vizan JL, 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(2):467–76.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    del Castillo FJ, del Castillo I, Moreno F. Construction and characterization of mutations at codon 751 of the Escherichia coli gyrB gene that confer resistance to the antimicrobial peptide microcin B17 and alter the activity of DNA gyrase. J Bacteriol. 2001;183(6):2137–40.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Thompson RE, Collin F, Maxwell A, Jolliffe KA, Payne RJ. Synthesis of full length and truncated microcin B17 analogues as DNA gyrase poisons. Org Biomol Chem. 2014;12(10):1570–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Collin F, Thompson RE, Jolliffe KA, Payne RJ, Maxwell A. Fragments of the bacterial toxin microcin b17 as gyrase poisons. PLoS One. 2013;8(4):e61459.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Thompson RE, Jolliffe KA, Payne RJ. Total synthesis of Microcin B17 via a fragment condensation approach. Org Lett. 2011;13(4):680–3.PubMedCrossRefGoogle Scholar
  57. 57.
    Videnov G, Kaiser D, Brooks M, Jung G. Synthesis of the DNA gyrase inhibitor microcin B17, a 43-peptie antibiotic with eight heterocycles in its backbone. Agnew Chem Int Ed Engl. 1996;35(13/14):1506–8.CrossRefGoogle Scholar
  58. 58.
    Trovatti E, Cotrim CA, Garrido SS, Barros RS, Marchetto R. Peptides based on CcdB protein as novel inhibitors of bacterial topoisomerases. Bioorg Med Chem Lett. 2008;18(23):6161–4.PubMedCrossRefGoogle Scholar
  59. 59.
    Walsh C, Wencewicz T. Antibiotics challenges mechanisms opportunites. Washington, DC: ASM Press; 2016. 477 p.Google Scholar
  60. 60.
    Heide L. The aminocoumarins: biosynthesis and biology. Nat Prod Rep. 2009;26(10):1241–50.PubMedCrossRefGoogle Scholar
  61. 61.
    Maxwell A, Lawson DM. The ATP-binding site of type II topoisomerases as a target for antibacterial drugs. Curr Top Med Chem. 2003;3(1):283–303.PubMedCrossRefGoogle Scholar
  62. 62.
    Mizuuchi K, O’Dea MH, Gellert M. DNA gyrase: subunit structure and ATPase activity of the purified enzyme. Proc Natl Acad Sci U S A. 1978;75:5960–3.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kato J, Suzuki H, Ikeda H. Purification and characterization of DNA topoisomerase IV in Escherichia coli. J Biol Chem. 1992;267(36):25676–84.PubMedGoogle Scholar
  64. 64.
    Wigley DB, Davies GJ, Dodson EJ, Maxwell A, Dodson G. Crystal structure of an N-terminal fragment of the DNA gyrase B protein. Nature. 1991;351(6328):624–9.PubMedCrossRefGoogle Scholar
  65. 65.
    Lewis RJ, Singh OM, Smith CV, Skarzynski T, Maxwell A, Wonacott AJ, et al. The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography. EMBO J. 1996;15(6):1412–20.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kampranis SC, Gormley NA, Tranter R, Orphanides G, Maxwell A. Probing the binding of coumarins and cyclothialidines to DNA gyrase. Biochemistry. 1999;38(7):1967–76.PubMedCrossRefGoogle Scholar
  67. 67.
    Dutta R, Inouye M. GHKL, an emergent ATPase/kinase superfamily. Trends Biochem Sci. 2000;25(1):24–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Burlison JA, Neckers L, Smith AB, Maxwell A, Blagg BS. Novobiocin: redesigning a DNA gyrase inhibitor for selective inhibition of Hsp90. J Am Chem Soc. 2006;128(48):15529–36.PubMedCrossRefGoogle Scholar
  69. 69.
    Heide L. Genetic engineering of antibiotic biosynthesis for the generation of new aminocoumarins. Biotechnol Adv. 2009;27(6):1006–14.PubMedCrossRefGoogle Scholar
  70. 70.
    Heide L. New aminocoumarin antibiotics as gyrase inhibitors. Int J Med Microbiol. 2014;304(1):31–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Eustaquio AS, Gust B, Luft T, Li SM, Chater KF, Heide L. Clorobiocin biosynthesis in Streptomyces. Identification of the halogenase and generation of structural analogs. Chem Biol. 2003;10(3):279–88.PubMedCrossRefGoogle Scholar
  72. 72.
    Anderle C, Stieger M, Burrell M, Reinelt S, Maxwell A, Page M, et al. Biological activities of novel gyrase inhibitors of the aminocoumarin class. Antimicrob Agents Chemother. 2008;52(6):1982–90.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Alt S, Burkard N, Kulik A, Grond S, Heide L. An artificial pathway to 3,4-dihydroxybenzoic acid allows generation of new aminocoumarin antibiotic recognized by catechol transporters of E. coli. Chem Biol. 2011;18(3):304–13.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Kamiyama T, Shimma N, Ohtsuka T, Nakayama N, Itezono Y, Nakada N, et al. Cyclothialidine, a novel DNA gyrase inhibitor. II. Isolation, characterization and structure elucidation. J Antibiot (Tokyo). 1994;47(1):37–45.CrossRefGoogle Scholar
  75. 75.
    Watanabe J, Nakada N, Sawairi S, Shimada H, Ohshima S, Kamiyama T, et al. Cyclothialidine, a novel DNA gyrase inhibitor. I. Screening, taxonomy, fermentation and biological activity. J Antibiot (Tokyo). 1994;47(1):32–6.CrossRefGoogle Scholar
  76. 76.
    Goetschi E, Angehrn P, Gmuender H, Hebeisen P, Link H, Masciadri R, et al. Cyclothialidine and its congeners: a new class of DNA gyrase inhibitors. Pharmacol Ther. 1993;60(2):367–80.PubMedCrossRefGoogle Scholar
  77. 77.
    Angehrn P, Buchmann S, Funk C, Goetschi E, Gmuender H, Hebeisen P, et al. New antibacterial agents derived from the DNA gyrase inhibitor cyclothialidine. J Med Chem. 2004;47(6):1487–513.PubMedCrossRefGoogle Scholar
  78. 78.
    Angehrn P, Goetschi E, Gmuender H, Hebeisen P, Hennig M, Kuhn B, et al. A new DNA gyrase inhibitor subclass of the cyclothialidine family based on a bicyclic dilactam-lactone scaffold. Synthesis and antibacterial properties. J Med Chem. 2011;54(7):2207–24.PubMedCrossRefGoogle Scholar
  79. 79.
    Theobald U, Schimana J, Fiedler HP. Microbial growth and production kinetics of Streptomyces antibioticus Tu 6040. Antonie Van Leeuwenhoek. 2000;78(3–4):307–13.PubMedCrossRefGoogle Scholar
  80. 80.
    Trefzer A, Pelzer S, Schimana J, Stockert S, Bihlmaier C, Fiedler HP, et al. Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic. Antimicrob Agents Chemother. 2002;46(5):1174–82.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Galm U, Schimana J, Fiedler HP, Schmidt J, Li SM, Heide L. Cloning and analysis of the simocyclinone biosynthetic gene cluster of Streptomyces antibioticus Tu 6040. Arch Microbiol. 2002;178(2):102–14.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Schimana J, Fiedler HP, Groth I, Sussmuth R, Beil W, Walker M, et al. Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tu 6040. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo). 2000;53(8):779–87.CrossRefGoogle Scholar
  83. 83.
    Schimana J, Walker M, Zeeck A, Fiedler P. Simocyclinones: diversity of metabolites is dependent on fermentation conditions. J Ind Microbiol Biotechnol. 2001;27(3):144–8.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Flatman RH, Howells AJ, Heide L, Fiedler HP, Maxwell A. Simocyclinone D8, an inhibitor of DNA gyrase with a novel mode of action. Antimicrob Agents Chemother. 2005;49(3):1093–100.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Le TB, Clarke TA, et al. A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science. 2009;326(5958):1415–8.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Edwards MJ, Williams MA, Maxwell A, McKay AR. Mass spectrometry reveals that the antibiotic simocyclinone D8 binds to DNA gyrase in a “bent-over” conformation: evidence of positive cooperativity in binding. Biochemistry. 2011;50(17):3432–40.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Hearnshaw SJ, Edwards MJ, Stevenson CE, Lawson DM, Maxwell A. A new crystal structure of the bifunctional antibiotic simocyclinone d8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. J Mol Biol. 2014;426(10):2023–33.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sissi C, Vazquez E, Chemello A, Mitchenall LA, Maxwell A, Palumbo M. Mapping simocyclinone D8 interaction with DNA gyrase: evidence for a new binding site on GyrB. Antimicrob Agents Chemother. 2010;54(1):213–20.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Richter SN, Frasson I, Palumbo M, Sissi C, Palu G. Simocyclinone D8 turns on against gram-negative bacteria in a clinical setting. Bioorg Med Chem Lett. 2010;20(3):1202–4.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Oppegard LM, Nguyen T, Ellis KC, Hiasa H. Inhibition of human topoisomerases I and II by simocyclinone D8. J Nat Prod. 2012;75(8):1485–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Sadiq AA, Patel MR, Jacobson BA, Escobedo M, Ellis K, Oppegard LM, et al. Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Investig New Drugs. 2009.Google Scholar
  92. 92.
    Austin MJ, Hearnshaw SJ, Mitchenall LA, McDermott PJ, Howell LA, Maxwell A, et al. A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents. MedChemComm. 2016;7(7):1387–91.CrossRefGoogle Scholar
  93. 93.
    Verghese J, Nguyen T, Oppegard LM, Seivert LM, Hiasa H, Ellis KC. Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors. Bioorg Med Chem Lett. 2013;23(21):5874–7.PubMedCrossRefGoogle Scholar
  94. 94.
    Bilyk O, Brotz E, Tokovenko B, Bechthold A, Paululat T, Luzhetskyy A. New simocyclinones: surprising evolutionary and biosynthetic insights. ACS Chem Biol. 2016;11(1):241–50.PubMedCrossRefGoogle Scholar
  95. 95.
    Mukherjee S, Robinson CA, Howe AG, Mazor T, Wood PA, Urgaonkar S, et al. N-Benzyl-3-sulfonamidopyrrolidines as novel inhibitors of cell division in E. coli. Bioorg Med Chem Lett. 2007;17(23):6651–5.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Foss MH, Hurley KA, Sorto N, Lackner LL, Thornton KM, Shaw JT, et al. N-Benzyl-3-sulfonamidopyrrolidines are a new class of bacterial DNA gyrase inhibitors. ACS Med Chem Lett. 2011;2(4):289–92.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Rajendram M, Hurley KA, Foss MH, Thornton KM, Moore JT, Shaw JT, et al. Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology. ACS Chem Biol. 2014;9(6):1312–9.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Hurley KA, Santos TMA, Fensterwald MR, Rajendran M, Moore JT, Balmond EI, et al. Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase. MedChemComm. 2017;8(5):942–51.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Pinto AV, de Castro SL. The trypanocidal activity of naphthoquinones: a review. Molecules. 2009;14(11):4570–90.PubMedCrossRefGoogle Scholar
  100. 100.
    van der Kooy F, Meyer JJM, Lall N. Antimycobacterial activity and possible mode of action of newly isolated neodiospyrin and other naphthoquinones from Euclea natalensis. S Afr J Bot. 2006;72(3):349–52.CrossRefGoogle Scholar
  101. 101.
    Lall N, Meyer JJM. Inhibition of drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis by diospyrin, isolated from Euclea natalensis. J Ethnopharmacol. 2001;78(2–3):213–6.PubMedCrossRefGoogle Scholar
  102. 102.
    Karkare S, Chung TT, Collin F, Mitchenall LA, McKay AR, Greive SJ, et al. The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action. J Biol Chem. 2013;288(7):5149–56.PubMedCrossRefGoogle Scholar
  103. 103.
    Phillips JW, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, et al. Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus. Chem Biol. 2011;18(8):955–65.PubMedCrossRefGoogle Scholar
  104. 104.
    Singh SB. Discovery and development of kibdelomycin, a new class of broad-spectrum antibiotics targeting the clinically proven bacterial type II topoisomerase. Bioorg Med Chem. 2016;24(24):6291–7.PubMedCrossRefGoogle Scholar
  105. 105.
    Singh SB, Dayananth P, Balibar CJ, Garlisi CG, Lu J, Kishii R, et al. Kibdelomycin is a bactericidal broad-spectrum aerobic antibacterial agent. Antimicrob Agents Chemother. 2015;59(6):3474–81.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Miesel L, Hecht DW, Osmolski JR, Gerding D, Flattery A, Li F, et al. Kibdelomycin is a potent and selective agent against toxigenic Clostridium difficile. Antimicrob Agents Chemother. 2014;58(4):2387–92.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Lu J, Patel S, Sharma N, Soisson SM, Kishii R, Takei M, et al. Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode. ACS Chem Biol. 2014;9(9):2023–31.PubMedCrossRefGoogle Scholar
  108. 108.
    Lincke T, Behnken S, Ishida K, Roth M, Hertweck C. Closthioamide: an unprecedented polythioamide antibiotic from the strictly anaerobic bacterium Clostridium cellulolyticum. Angew Chem Int Ed Engl. 2010;49(11):2011–3.PubMedCrossRefGoogle Scholar
  109. 109.
    Chiriac AI, Kloss F, Kramer J, Vuong C, Hertweck C, Sahl HG. Mode of action of closthioamide: the first member of the polythioamide class of bacterial DNA gyrase inhibitors. J Antimicrob Chemother. 2015;70(9):2576–88.CrossRefGoogle Scholar
  110. 110.
    Sawa R, Takahashi Y, Hashizume H, Sasaki K, Ishizaki Y, Umekita M, et al. Amycolamicin: a novel broad-spectrum antibiotic inhibiting bacterial topoisomerase. Chemistry. 2012;18(49):15772–81.PubMedCrossRefGoogle Scholar
  111. 111.
    Agrawal A, Roue M, Spitzfaden C, Petrella S, Aubry A, Hann M, et al. Mycobacterium tuberculosis DNA gyrase ATPase domain structures suggest a dissociative mechanism that explains how ATP hydrolysis is coupled to domain motion. Biochem J. 2013;456(2):263–73.PubMedCrossRefGoogle Scholar
  112. 112.
    Hearnshaw SJ, Chung TT, Stevenson CE, Maxwell A, Lawson DM. The role of monovalent cations in the ATPase reaction of DNA gyrase. Acta Crystallogr D Biol Crystallogr. 2015;71(Pt 4):996–1005.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Stanger FV, Dehio C, Schirmer T. Structure of the N-terminal gyrase B fragment in complex with ADPPi reveals rigid-body motion induced by ATP hydrolysis. PLoS One. 2014;9(9):e107289.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Lewis RJ, Singh OM, Smith CV, Maxwell A, Skarzynski T, Wonacott AJ, et al. Crystallization of inhibitor complexes of an N-terminal 24 kDa fragment of the DNA gyrase B protein. J Mol Biol. 1994;241(1):128–30.PubMedCrossRefGoogle Scholar
  115. 115.
    Tsai FT, Singh OM, Skarzynski T, Wonacott AJ, Weston S, Tucker A, et al. The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins. 1997;28(1):41–52.PubMedCrossRefGoogle Scholar
  116. 116.
    Bellon S, Parsons JD, Wei Y, Hayakawa K, Swenson LL, Charifson PS, et al. Crystal structures of Escherichia coli topoisomerase IV ParE subunit (24 and 43 kilodaltons): a single residue dictates differences in novobiocin potency against topoisomerase IV and DNA gyrase. Antimicrob Agents Chemother. 2004;48(5):1856–64.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Oblak M, Kotnik M, Solmajer T. Discovery and development of ATPase inhibitors of DNA gyrase as antibacterial agents. Curr Med Chem. 2007;14(19):2033–47.PubMedCrossRefGoogle Scholar
  118. 118.
    Garg G, Zhao H, Blagg BSJ. Design, synthesis, and biological evaluation of ring-constrained Novobiocin analogues as Hsp90 C-terminal inhibitors. ACS Med Chem Lett. 2014.Google Scholar
  119. 119.
    Hall JA, Seedarala S, Zhao H, Garg G, Ghosh S, Blagg BS. Novobiocin analogues that inhibit the MAPK pathway. J Med Chem. 2016;59(3):925–33.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kampranis SC, Bates AD, Maxwell A. A model for the mechanism of strand passage by DNA gyrase. Proc Natl Acad Sci U S A. 1999;96(15):8414–9.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Morris SK, Baird CL, Lindsley JE. Steady-state and rapid kinetic analysis of topoisomerase II trapped as the closed-clamp intermediate by ICRF-193. J Biol Chem. 2000;275(4):2613–8.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Ehmann DE, Lahiri SD. Novel compounds targeting bacterial DNA topoisomerase/DNA gyrase. Curr Opin Pharmacol. 2014;18:76–83.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Boehm HJ, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W, et al. Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J Med Chem. 2000;43(14):2664–74.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, et al. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Bioorg Med Chem Lett. 2016;26(4):1314–8.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Cross JB, Zhang J, Yang Q, Mesleh MF, Romero JA, Wang B, et al. Discovery of pyrazolopyridones as a novel class of gyrase B inhibitors using structure guided design. ACS Med Chem Lett. 2016;7(4):374–8.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Zhang J, Yang Q, Cross JB, Romero JA, Poutsiaka KM, Epie F, et al. Discovery of Azaindole Ureas as a novel class of bacterial gyrase B inhibitors. J Med Chem. 2015;58(21):8503–12.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Eakin AE, Green O, Hales N, Walkup GK, Bist S, Singh A, et al. Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents. Antimicrob Agents Chemother. 2012;56(3):1240–6.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Jeankumar VU, Renuka J, Kotagiri S, Saxena S, Kakan SS, Sridevi JP, et al. Gyrase ATPase domain as an antitubercular drug discovery platform: structure-based design and lead optimization of nitrothiazolyl carboxamide analogues. ChemMedChem. 2014;9(8):1850–9.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Jeankumar VU, Saxena S, Vats R, Reshma RS, Janupally R, Kulkarni P, et al. Structure-guided discovery of antitubercular agents that target the gyrase ATPase domain. ChemMedChem. 2016;11(5):539–48.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Jeankumar VU, Reshma RS, Vats R, Janupally R, Saxena S, Yogeeswari P, et al. Engineering another class of anti-tubercular lead: hit to lead optimization of an intriguing class of gyrase ATPase inhibitors. Eur J Med Chem. 2016;122:216–31.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Saxena S, Samala G, Renuka J, Sridevi JP, Yogeeswari P, Sriram D. Development of 2-amino-5-phenylthiophene-3-carboxamide derivatives as novel inhibitors of Mycobacterium tuberculosis DNA GyrB domain. Bioorg Med Chem. 2015;23(7):1402–12.PubMedCrossRefGoogle Scholar
  132. 132.
    Gjorgjieva M, Tomasic T, Barancokova M, Katsamakas S, Ilas J, Tammela P, et al. Discovery of benzothiazole scaffold-based DNA gyrase B inhibitors. J Med Chem. 2016;59(19):8941–54.PubMedCrossRefGoogle Scholar
  133. 133.
    Jakopin Z, Ilas J, Barancokova M, Brvar M, Tammela P, Sollner Dolenc M, et al. Discovery of substituted oxadiazoles as a novel scaffold for DNA gyrase inhibitors. Eur J Med Chem. 2017;130:171–84.PubMedCrossRefGoogle Scholar
  134. 134.
    Sun J, Lv PC, Yin Y, Yuan RJ, Ma J, Zhu HL. Synthesis, structure and antibacterial activity of potent DNA gyrase inhibitors: N'-benzoyl-3-(4-bromophenyl)-1H-pyrazole-5-carbohydrazide derivatives. PLoS One. 2013;8(7):e69751.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    O'Brien S. Meeting the societal need for new antibiotics: the challenges for the pharmaceutical industry. Br J Clin Pharmacol. 2015;79(2):168–72.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Bax R, Green S. Antibiotics: the changing regulatory and pharmaceutical industry paradigm. J Antimicrob Chemother. 2015;70(5):1281–4.PubMedCrossRefGoogle Scholar
  137. 137.
    Silver LL. Challenges of antibacterial discovery. Clin Microbiol Rev. 2011;24(1):71–109.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Cooper MA, Shlaes D. Fix the antibiotics pipeline. Nature. 2011;472(7341):32.PubMedCrossRefGoogle Scholar
  139. 139.
    Payne DJ, Miller LF, Findlay D, Anderson J, Marks L. Time for a change: addressing R&D and commercialization challenges for antibacterials. Philos Trans R Soc Lond Ser B Biol Sci. 2015;370(1670):20140086.CrossRefGoogle Scholar
  140. 140.
    Kostyanev T, Bonten MJ, O'Brien S, Steel H, Ross S, Francois B, et al. The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance. J Antimicrob Chemother. 2016;71(2):290–5.PubMedCrossRefGoogle Scholar
  141. 141.
    Candel FJ, Penuelas M. Delafloxacin: design, development and potential place in therapy. Drug Des Devel Ther. 2017;11:881–91.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Basarab GS, Brassil P, Doig P, Galullo V, Haimes HB, Kern G, et al. Novel DNA gyrase inhibiting spiropyrimidinetriones with a benzisoxazole scaffold: SAR and in vivo characterization. J Med Chem. 2014;57(21):9078–95.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Charifson PS, Grillot AL, Grossman TH, Parsons JD, Badia M, Bellon S, et al. Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and structure-activity relationships. J Med Chem. 2008;51(17):5243–63.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Anthony Maxwell
    • 1
    Email author
  • Natassja G. Bush
    • 1
  • Thomas Germe
    • 1
  • Shannon J. McKie
    • 1
  1. 1.Department of Biological Chemistry, John Innes CentreNorwich Research ParkNorwichUK

Personalised recommendations