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A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase.

Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Le TB, Clarke TA, McKay AR, Fiedler HP, Buttner MJ, Lawson DM, Maxwell A
Science 326 1415-8 (2009)
Cited: 50 times
EuropePMC logo PMID: 19965760

Abstract

Simocyclinones are bifunctional antibiotics that inhibit bacterial DNA gyrase by preventing DNA binding to the enzyme. We report the crystal structure of the complex formed between the N-terminal domain of the Escherichia coli gyrase A subunit and simocyclinone D8, revealing two binding pockets that separately accommodate the aminocoumarin and polyketide moieties of the antibiotic. These are close to, but distinct from, the quinolone-binding site, consistent with our observations that several mutations in this region confer resistance to both agents. Biochemical studies show that the individual moieties of simocyclinone D8 are comparatively weak inhibitors of gyrase relative to the parent compound, but their combination generates a more potent inhibitor. Our results should facilitate the design of drug molecules that target these unexploited binding pockets.

Reviews - 2y3p mentioned but not cited (1)

  1. Topoisomerases as anticancer targets. Delgado JL, Hsieh CM, Chan NL, Hiasa H. Biochem J 475 373-398 (2018)

Articles - 2y3p mentioned but not cited (3)

  1. A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. Hearnshaw SJ, Edwards MJ, Stevenson CE, Lawson DM, Maxwell A. J Mol Biol 426 2023-2033 (2014)
  2. Identification of novel bacterial DNA gyrase inhibitors: An in silico study. Rahimi H, Najafi A, Eslami H, Negahdari B, Moghaddam MM. Res Pharm Sci 11 250-258 (2016)
  3. s-Triazine Derivatives Functionalized with Alkylating 2-Chloroethylamine Fragments as Promising Antimicrobial Agents: Inhibition of Bacterial DNA Gyrases, Molecular Docking Studies, and Antibacterial and Antifungal Activity. Maliszewski D, Demirel R, Wróbel A, Baradyn M, Ratkiewicz A, Drozdowska D. Pharmaceuticals (Basel) 16 1248 (2023)


Reviews citing this publication (13)

  1. All tangled up: how cells direct, manage and exploit topoisomerase function. Vos SM, Tretter EM, Schmidt BH, Berger JM. Nat Rev Mol Cell Biol 12 827-841 (2011)
  2. The TetR family of regulators. Cuthbertson L, Nodwell JR. Microbiol Mol Biol Rev 77 440-475 (2013)
  3. Exploiting bacterial DNA gyrase as a drug target: current state and perspectives. Collin F, Karkare S, Maxwell A. Appl Microbiol Biotechnol 92 479-497 (2011)
  4. New mechanistic and functional insights into DNA topoisomerases. Chen SH, Chan NL, Hsieh TS. Annu Rev Biochem 82 139-170 (2013)
  5. Interfacial inhibitors: targeting macromolecular complexes. Pommier Y, Marchand C. Nat Rev Drug Discov 11 25-36 (2011)
  6. Combination therapies for combating antimicrobial resistance. Fischbach MA. Curr Opin Microbiol 14 519-523 (2011)
  7. In front of and behind the replication fork: bacterial type IIA topoisomerases. Sissi C, Palumbo M. Cell Mol Life Sci 67 2001-2024 (2010)
  8. New aminocoumarin antibiotics as gyrase inhibitors. Heide L. Int J Med Microbiol 304 31-36 (2014)
  9. Recent progress in the discovery and development of DNA gyrase B inhibitors. Barančoková M, Kikelj D, Ilaš J. Future Med Chem 10 1207-1227 (2018)
  10. The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery. Kaguni JM. Antibiotics (Basel) 7 E23 (2018)
  11. Single-molecule FRET reveals nucleotide-driven conformational changes in molecular machines and their link to RNA unwinding and DNA supercoiling. Klostermeier D. Biochem Soc Trans 39 611-616 (2011)
  12. Structural insights into simocyclinone as an antibiotic, effector ligand and substrate. Buttner MJ, Schäfer M, Lawson DM, Maxwell A. FEMS Microbiol Rev 42 (2018)
  13. Towards Conformation-Sensitive Inhibition of Gyrase: Implications of Mechanistic Insight for the Identification and Improvement of Inhibitors. Klostermeier D. Molecules 26 1234 (2021)

Articles citing this publication (33)

  1. Type IIA topoisomerase inhibition by a new class of antibacterial agents. Bax BD, Chan PF, Eggleston DS, Fosberry A, Gentry DR, Gorrec F, Giordano I, Hann MM, Hennessy A, Hibbs M, Huang J, Jones E, Jones J, Brown KK, Lewis CJ, May EW, Saunders MR, Singh O, Spitzfaden CE, Shen C, Shillings A, Theobald AJ, Wohlkonig A, Pearson ND, Gwynn MN. Nature 466 935-940 (2010)
  2. Structural insights into the quinolone resistance mechanism of Mycobacterium tuberculosis DNA gyrase. Piton J, Petrella S, Delarue M, André-Leroux G, Jarlier V, Aubry A, Mayer C. PLoS One 5 e12245 (2010)
  3. Inhibition of DNA gyrase and DNA topoisomerase IV of Staphylococcus aureus and Escherichia coli by aminocoumarin antibiotics. Alt S, Mitchenall LA, Maxwell A, Heide L. J Antimicrob Chemother 66 2061-2069 (2011)
  4. A domain insertion in Escherichia coli GyrB adopts a novel fold that plays a critical role in gyrase function. Schoeffler AJ, May AP, Berger JM. Nucleic Acids Res 38 7830-7844 (2010)
  5. SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. Horbal L, Rebets Y, Rabyk M, Makitrynskyy R, Luzhetskyy A, Fedorenko V, Bechthold A. AMB Express 2 1 (2012)
  6. The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding. Le TB, Schumacher MA, Lawson DM, Brennan RG, Buttner MJ. Nucleic Acids Res 39 9433-9447 (2011)
  7. Harnessing evolutionary fitness in Plasmodium falciparum for drug discovery and suppressing resistance. Lukens AK, Ross LS, Heidebrecht R, Javier Gamo F, Lafuente-Monasterio MJ, Booker ML, Hartl DL, Wiegand RC, Wirth DF. Proc Natl Acad Sci U S A 111 799-804 (2014)
  8. A natural plasmid uniquely encodes two biosynthetic pathways creating a potent anti-MRSA antibiotic. Fukuda D, Haines AS, Song Z, Murphy AC, Hothersall J, Stephens ER, Gurney R, Cox RJ, Crosby J, Willis CL, Simpson TJ, Thomas CM. PLoS One 6 e18031 (2011)
  9. Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus. Schröder W, Goerke C, Wolz C. J Antimicrob Chemother 68 529-538 (2013)
  10. The naphthoquinone diospyrin is an inhibitor of DNA gyrase with a novel mechanism of action. Karkare S, Chung TT, Collin F, Mitchenall LA, McKay AR, Greive SJ, Meyer JJ, Lall N, Maxwell A. J Biol Chem 288 5149-5156 (2013)
  11. Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. MK844-mF10. Igarashi M, Watanabe T, Hashida T, Umekita M, Hatano M, Yanagida Y, Kino H, Kimura T, Kinoshita N, Inoue K, Sawa R, Nishimura Y, Utsumi R, Nomoto A. J Antibiot (Tokyo) 66 459-464 (2013)
  12. Structures of the TetR-like simocyclinone efflux pump repressor, SimR, and the mechanism of ligand-mediated derepression. Le TB, Stevenson CE, Fiedler HP, Maxwell A, Lawson DM, Buttner MJ. J Mol Biol 408 40-56 (2011)
  13. Fragments of the bacterial toxin microcin B17 as gyrase poisons. Collin F, Thompson RE, Jolliffe KA, Payne RJ, Maxwell A. PLoS One 8 e61459 (2013)
  14. New aminocoumarins from the rare actinomycete Catenulispora acidiphila DSM 44928: identification, structure elucidation, and heterologous production. Zettler J, Xia H, Burkard N, Kulik A, Grond S, Heide L, Apel AK. Chembiochem 15 612-621 (2014)
  15. Application of a novel microtitre plate-based assay for the discovery of new inhibitors of DNA gyrase and DNA topoisomerase VI. Taylor JA, Mitchenall LA, Rejzek M, Field RA, Maxwell A. PLoS One 8 e58010 (2013)
  16. Characterisation of novel mutations involved in quinolone resistance in Escherichia coli isolated from imported shrimp. Nawaz M, Sung K, Kweon O, Khan S, Nawaz S, Steele R. Int J Antimicrob Agents 45 471-476 (2015)
  17. Research Support, Non-U.S. Gov't Advances in structure-based drug design of novel bacterial topoisomerase inhibitors. Widdowson K, Hennessy A. Future Med Chem 2 1619-1622 (2010)
  18. Altering gene expression by aminocoumarins: the role of DNA supercoiling in Staphylococcus aureus. Schröder W, Bernhardt J, Marincola G, Klein-Hitpass L, Herbig A, Krupp G, Nieselt K, Wolz C. BMC Genomics 15 291 (2014)
  19. Mapping simocyclinone D8 interaction with DNA gyrase: evidence for a new binding site on GyrB. Sissi C, Vazquez E, Chemello A, Mitchenall LA, Maxwell A, Palumbo M. Antimicrob Agents Chemother 54 213-220 (2010)
  20. Protective effect of Qnr on agents other than quinolones that target DNA gyrase. Jacoby GA, Corcoran MA, Hooper DC. Antimicrob Agents Chemother 59 6689-6695 (2015)
  21. Identification of Genome-Wide Mutations in Ciprofloxacin-Resistant F. tularensis LVS Using Whole Genome Tiling Arrays and Next Generation Sequencing. Jaing CJ, McLoughlin KS, Thissen JB, Zemla A, Gardner SN, Vergez LM, Bourguet F, Mabery S, Fofanov VY, Koshinsky H, Jackson PJ. PLoS One 11 e0163458 (2016)
  22. Substrate-Assisted Catalysis in Polyketide Reduction Proceeds via a Phenolate Intermediate. Schäfer M, Stevenson CEM, Wilkinson B, Lawson DM, Buttner MJ. Cell Chem Biol 23 1091-1097 (2016)
  23. Investigation of Nalidixic Acid Resistance Mechanism in Salmonella enterica Using Molecular Simulation Techniques. Preethi B, Shanthi V, Ramanathan K. Appl Biochem Biotechnol 177 528-540 (2015)
  24. A docking-based receptor library of antibiotics and its novel application in predicting chronic mixture toxicity for environmental risk assessment. Zou X, Zhou X, Lin Z, Deng Z, Yin D. Environ Monit Assess 185 4513-4527 (2013)
  25. Flavone-based analogues inspired by the natural product simocyclinone D8 as DNA gyrase inhibitors. Verghese J, Nguyen T, Oppegard LM, Seivert LM, Hiasa H, Ellis KC. Bioorg Med Chem Lett 23 5874-5877 (2013)
  26. SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone. Schäfer M, Le TB, Hearnshaw SJ, Maxwell A, Challis GL, Wilkinson B, Buttner MJ. J Mol Biol 427 2192-2204 (2015)
  27. Molecular level understanding of resistance to nalidixic acid in Salmonella enteric serovar typhimurium associates with the S83F sequence type. Preethi B, Ramanathan K. Eur Biophys J 45 35-44 (2016)
  28. New N-(2-phenyl-4-oxo-1,3-thiazolidin-3-yl)-1,2-benzothiazole-3-carboxamides and acetamides as antimicrobial agents. Incerti M, Vicini P, Geronikaki A, Eleftheriou P, Tsagkadouras A, Zoumpoulakis P, Fotakis C, Ćirić A, Glamočlija J, Soković M. Medchemcomm 8 2142-2154 (2017)
  29. Characterization of the Biosynthetic Gene Cluster and Shunt Products Yields Insights into the Biosynthesis of Balmoralmycin. Ma GL, Xin L, Liao Y, Chong ZS, Candra H, Pang LM, Lee SQE, Gakuubi MM, Ng SB, Liang ZX. Appl Environ Microbiol 88 e0120822 (2022)
  30. Crystallization and preliminary X-ray analysis of the TetR-like efflux pump regulator SimR. Le TB, Stevenson CE, Buttner MJ, Lawson DM. Acta Crystallogr Sect F Struct Biol Cryst Commun 67 307-309 (2011)
  31. Inhibition of Isoleucyl-tRNA Synthetase by the Hybrid Antibiotic Thiomarinol. Johnson RA, Chan AN, Ward RD, McGlade CA, Hatfield BM, Peters JM, Li B. J Am Chem Soc 143 12003-12013 (2021)
  32. Targeting quinolone- and aminocoumarin-resistant bacteria with new gyramide analogs that inhibit DNA gyrase. Hurley KA, Santos TMA, Fensterwald MR, Rajendran M, Moore JT, Balmond EI, Blahnik BJ, Faulkner KC, Foss MH, Heinrich VA, Lammers MG, Moore LC, Reynolds GD, Shearn-Nance GP, Stearns BA, Yao ZW, Shaw JT, Weibel DB. Medchemcomm 8 942-951 (2017)
  33. [Dual attack on the gyrase by simocyclinone]. Holzgrabe U. Pharm Unserer Zeit 39 95-96 (2010)


Related citations provided by authors (1)

  1. Crystallization and preliminary X-ray analysis of a complex formed between the antibiotic simocyclinone D8 and the DNA breakage-reunion domain of Escherichia coli DNA gyrase.. Edwards MJ, Flatman RH, Mitchenall LA, Stevenson CE, Maxwell A, Lawson DM Acta Crystallogr Sect F Struct Biol Cryst Commun 65 846-8 (2009)

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