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Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin.

<div class='caption-title'>Schematics of S. aureus DNA gyrase cleavage complexes with inhibitors.</div>
<div class='caption-title'>S. aureus gyrase DNA-cleavage activity and crystal structures with three different inhibitors.</div>
<div class='caption-title'>Binding sites for QPT-1, etoposide and moxifloxacin in S. aureus DNA gyrase complexes.</div>
Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, Hann MM, Hibbs M, Homes P, Ingraham K, Pizzollo J, Shen C, Shillings AJ, Spitzfaden CE, Tanner R, Theobald AJ, Stavenger RA, Bax BD, Gwynn MN
OpenAccess logo Nat Commun 6 10048 (2015)
Related entries: 5cdm, 5cdn, 5cdo, 5cdp, 5cdq

Cited: 47 times
EuropePMC logo PMID: 26640131

Abstract

New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide's antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a 'pair of swing-doors' hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1's bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.

Reviews - 5cdr mentioned but not cited (1)

  1. DNA Topoisomerase Inhibitors: Trapping a DNA-Cleaving Machine in Motion. Bax BD, Murshudov G, Maxwell A, Germe T. J Mol Biol 431 3427-3449 (2019)

Articles - 5cdr mentioned but not cited (2)

  1. Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin. Chan PF, Srikannathasan V, Huang J, Cui H, Fosberry AP, Gu M, Hann MM, Hibbs M, Homes P, Ingraham K, Pizzollo J, Shen C, Shillings AJ, Spitzfaden CE, Tanner R, Theobald AJ, Stavenger RA, Bax BD, Gwynn MN. Nat Commun 6 10048 (2015)
  2. Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide. Srikannathasan V, Wohlkonig A, Shillings A, Singh O, Chan PF, Huang J, Gwynn MN, Fosberry AP, Homes P, Hibbs M, Theobald AJ, Spitzfaden C, Bax BD. Acta Crystallogr F Struct Biol Commun 71 1242-1246 (2015)


Reviews citing this publication (9)

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  2. The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity. Naeem A, Badshah SL, Badshah SL, Muska M, Ahmad N, Khan K. Molecules 21 268 (2016)
  3. The Microbial Toxin Microcin B17: Prospects for the Development of New Antibacterial Agents. Collin F, Maxwell A. J Mol Biol 431 3400-3426 (2019)
  4. The Macromolecular Machines that Duplicate the Escherichia coli Chromosome as Targets for Drug Discovery. Kaguni JM. Antibiotics (Basel) 7 E23 (2018)
  5. Keep it together: restraints in crystallographic refinement of macromolecule-ligand complexes. Steiner RA, Tucker JA. Acta Crystallogr D Struct Biol 73 93-102 (2017)
  6. Towards Conformation-Sensitive Inhibition of Gyrase: Implications of Mechanistic Insight for the Identification and Improvement of Inhibitors. Klostermeier D. Molecules 26 1234 (2021)
  7. Developments in Non-Intercalating Bacterial Topoisomerase Inhibitors: Allosteric and ATPase Inhibitors of DNA Gyrase and Topoisomerase IV. Grossman S, Fishwick CWG, McPhillie MJ. Pharmaceuticals (Basel) 16 261 (2023)
  8. Oligonucleotide-Recognizing Topoisomerase Inhibitors (OTIs): Precision Gene Editors for Neurodegenerative Diseases? Bax BD, Sutormin D, McDonald NQ, Burley GA, Shelkovnikova T. Int J Mol Sci 23 11541 (2022)
  9. Small molecule inducers of actinobacteria natural product biosynthesis. Alwali AY, Parkinson EI. J Ind Microbiol Biotechnol 50 kuad019 (2023)

Articles citing this publication (35)

  1. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase. Gibson EG, Bax B, Chan PF, Osheroff N. ACS Infect Dis 5 570-581 (2019)
  2. Getting the chemistry right: protonation, tautomers and the importance of H atoms in biological chemistry. Bax B, Chung CW, Edge C. Acta Crystallogr D Struct Biol 73 131-140 (2017)
  3. Thiophene antibacterials that allosterically stabilize DNA-cleavage complexes with DNA gyrase. Chan PF, Germe T, Bax BD, Huang J, Thalji RK, Bacqué E, Checchia A, Chen D, Cui H, Ding X, Ingraham K, McCloskey L, Raha K, Srikannathasan V, Maxwell A, Stavenger RA. Proc Natl Acad Sci U S A 114 E4492-E4500 (2017)
  4. Mechanism of Action of Mycobacterium tuberculosis Gyrase Inhibitors: A Novel Class of Gyrase Poisons. Gibson EG, Blower TR, Cacho M, Bax B, Berger JM, Osheroff N. ACS Infect Dis 4 1211-1222 (2018)
  5. A new class of antibacterials, the imidazopyrazinones, reveal structural transitions involved in DNA gyrase poisoning and mechanisms of resistance. Germe T, Vörös J, Jeannot F, Taillier T, Stavenger RA, Bacqué E, Maxwell A, Bax BD. Nucleic Acids Res 46 4114-4128 (2018)
  6. Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences. Infante Lara L, Fenner S, Ratcliffe S, Isidro-Llobet A, Hann M, Bax B, Osheroff N. Nucleic Acids Res 46 2218-2233 (2018)
  7. Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase. Laponogov I, Pan XS, Veselkov DA, Skamrova GB, Umrekar TR, Fisher LM, Sanderson MR. Nat Commun 9 2579 (2018)
  8. Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds. Kolarič A, Germe T, Hrast M, Stevenson CEM, Lawson DM, Burton NP, Vörös J, Maxwell A, Minovski N, Anderluh M. Nat Commun 12 150 (2021)
  9. Discovery of a Novel DNA Gyrase-Targeting Antibiotic through the Chemical Perturbation of Streptomyces venezuelae Sporulation. McAuley S, Huynh A, Howells A, Walpole C, Maxwell A, Nodwell JR. Cell Chem Biol 26 1274-1282.e4 (2019)
  10. Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones. Laponogov I, Pan XS, Veselkov DA, Cirz RT, Wagman A, Moser HE, Fisher LM, Sanderson MR. Open Biol 6 160157 (2016)
  11. Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones. Basarab GS, Ghorpade S, Gibhard L, Mueller R, Njoroge M, Peton N, Govender P, Massoudi LM, Robertson GT, Lenaerts AJ, Boshoff HI, Joerss D, Parish T, Durand-Reville TF, Perros M, Singh V, Chibale K. Antimicrob Agents Chemother 66 e0219221 (2022)
  12. Suppression of gyrase-mediated resistance by C7 aryl fluoroquinolones. Malik M, Mustaev A, Schwanz HA, Luan G, Shah N, Oppegard LM, de Souza EC, Hiasa H, Zhao X, Kerns RJ, Drlica K. Nucleic Acids Res 44 3304-3316 (2016)
  13. Sanguiin H-6 Fractionated from Cloudberry (Rubus chamaemorus) Seeds Can Prevent the Methicillin-Resistant Staphylococcus aureus Biofilm Development during Wound Infection. Aguilera-Correa JJ, Fernández-López S, Cuñas-Figueroa ID, Pérez-Rial S, Alakomi HL, Nohynek L, Oksman-Caldentey KM, Salminen JP, Esteban J, Cuadros J, Puupponen-Pimiä R, Perez-Tanoira R, Kinnari TJ. Antibiotics (Basel) 10 1481 (2021)
  14. Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity. Govender P, Müller R, Singh K, Reddy V, Eyermann CJ, Fienberg S, Ghorpade SR, Koekemoer L, Myrick A, Schnappinger D, Engelhart C, Meshanni J, Byl JAW, Osheroff N, Singh V, Chibale K, Basarab GS. J Med Chem 65 6903-6925 (2022)
  15. Novel Bacterial Topoisomerase Inhibitors Exploit Asp83 and the Intrinsic Flexibility of the DNA Gyrase Binding Site. Franco-Ulloa S, La Sala G, Miscione GP, De Vivo M. Int J Mol Sci 19 E453 (2018)
  16. The antibacterial agent, moxifloxacin inhibits virulence factors of Candida albicans through multitargeting. Jadhav A, Bansode B, Phule D, Shelar A, Patil R, Gade W, Kharat K, Karuppayil SM. World J Microbiol Biotechnol 33 96 (2017)
  17. A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase. Morgan H, Lipka-Lloyd M, Warren AJ, Hughes N, Holmes J, Burton NP, Mahenthiralingam E, Bax BD. Int J Mol Sci 24 1634 (2023)
  18. Replication and partitioning of the apicoplast genome of Toxoplasma gondii is linked to the cell cycle and requires DNA polymerase and gyrase. Martins-Duarte ÉS, Sheiner L, Reiff SB, de Souza W, Striepen B. Int J Parasitol 51 493-504 (2021)
  19. Hybrid Inhibitors of DNA Gyrase A and B: Design, Synthesis and Evaluation. Durcik M, Skok Ž, Ilaš J, Zidar N, Zega A, Szili PÉ, Draskovits G, Révész T, Kikelj D, Nyerges A, Pál C, Mašič LP, Tomašič T. Pharmaceutics 13 E6 (2020)
  20. A potent antibiotic-loaded bone-cement implant against staphylococcal bone infections. Ghosh S, Sinha M, Samanta R, Sadhasivam S, Bhattacharyya A, Nandy A, Saini S, Tandon N, Singh H, Gupta S, Chauhan A, Aavula KK, Varghese SS, Shi P, Ghosh S, Garg MK, Saha T, Padhye A, Ghosh S, Jang HL, Sengupta S. Nat Biomed Eng 6 1180-1195 (2022)
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  22. Design, Synthesis, in vitro and in silico Characterization of 2-Quinolone-L-alaninate-1,2,3-triazoles as Antimicrobial Agents. Moussaoui O, Bhadane R, Sghyar R, Ilaš J, El Hadrami EM, Chakroune S, Salo-Ahen OMH. ChemMedChem 17 e202100714 (2022)
  23. New marine-derived indolymethyl pyrazinoquinazoline alkaloids with promising antimicrobial profiles. Long S, Resende DISP, Palmeira A, Kijjoa A, Silva AMS, Tiritan ME, Pereira-Terra P, Freitas-Silva J, Barreiro S, Silva R, Remião F, Pinto E, Martins da Costa P, Sousa E, Pinto MMM. RSC Adv 10 31187-31204 (2020)
  24. The Effect of Conjugation with Octaarginine, a Cell-Penetrating Peptide on Antifungal Activity of Imidazoacridinone Derivative. Rząd K, Paluszkiewicz E, Neubauer D, Olszewski M, Kozłowska-Tylingo K, Kamysz W, Gabriel I. Int J Mol Sci 22 13190 (2021)
  25. Chemoselective syntheses of spirodihydrofuryl and spirocyclopropyl barbiturates via cascade reactions of barbiturate-based olefins and acetylacetone. Yan X, Shao P, Song X, Zhang C, Lu C, Liu S, Li Y. Org Biomol Chem 17 2684-2690 (2019)
  26. Efficient construction of tetrahydroquinolines via fluorinated alcohol mediated cascade [1,5]-hydride transfer/cyclization. Chen C, Xu L, Wang L, Li SS. Org Biomol Chem 16 7109-7114 (2018)
  27. Novel ciprofloxacin and norfloxacin-tetrazole hybrids as potential antibacterial and antiviral agents: Targeting S. aureus topoisomerase and SARS-CoV-2-MPro. Cardoso-Ortiz J, Leyva-Ramos S, Baines KM, Gómez-Durán CFA, Hernández-López H, Palacios-Can FJ, Valcarcel-Gamiño JA, Leyva-Peralta MA, Razo-Hernández RS. J Mol Struct 1274 134507 (2023)
  28. Palladium(II) Complexes of Substituted Salicylaldehydes: Synthesis, Characterization and Investigation of Their Biological Profile. Zianna A, Geromichalos G, Fiotaki AM, Hatzidimitriou AG, Kalogiannis S, Psomas G. Pharmaceuticals (Basel) 15 886 (2022)
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  30. Synthesis and Decarboxylation of Functionalized 2-Pyridone-3-carboxylic Acids and Evaluation of their Antimicrobial Activity and Molecular Docking. Meghrazi Ahadi E, Azizian H, Fathi Vavsari V, Aliahmadi A, Shahsavari Z, Bijanzadeh HR, Balalaie S. Iran J Pharm Res 20 456-475 (2021)
  31. A Series of Spiropyrimidinetriones that Enhances DNA Cleavage Mediated by Mycobacterium tuberculosis Gyrase. Byl JAW, Mueller R, Bax B, Basarab GS, Chibale K, Osheroff N. ACS Infect Dis 9 706-715 (2023)
  32. Actions of a Novel Bacterial Topoisomerase Inhibitor against Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks. Dauda SE, Collins JA, Byl JAW, Lu Y, Yalowich JC, Mitton-Fry MJ, Osheroff N. Int J Mol Sci 24 12107 (2023)
  33. Fluoroquinolone Analogs, SAR Analysis, and the Antimicrobial Evaluation of 7-Benzimidazol-1-yl-fluoroquinolone in In Vitro, In Silico, and In Vivo Models. Medellín-Luna MF, Hernández-López H, Castañeda-Delgado JE, Martinez-Gutierrez F, Lara-Ramírez E, Espinoza-Rodríguez JJ, García-Cruz S, Portales-Pérez DP, Cervantes-Villagrana AR. Molecules 28 6018 (2023)
  34. Investigation of Novel Quinoline-Thiazole Derivatives as Antimicrobial Agents: In Vitro and In Silico Approaches. Evren AE, Karaduman AB, Sağlik BN, Özkay Y, Yurttaş L. ACS Omega 8 1410-1429 (2023)
  35. Mitoxantrone targets both host and bacteria to overcome vancomycin resistance in Enterococcus faecalis. da Silva RAG, Wong JJ, Antypas H, Choo PY, Goh K, Jolly S, Liang C, Tay Kwan Sing L, Veleba M, Hu G, Chen J, Kline KA. Sci Adv 9 eadd9280 (2023)


Related citations provided by authors (1)

  1. Crystallization and initial crystallographic analysis of covalent DNA-cleavage complexes of Staphyloccocus aureus DNA gyrase with QPT-1, moxifloxacin and etoposide.. Srikannathasan V, Wohlkonig A, Shillings A, Singh O, Chan PF, Huang J, Gwynn MN, Fosberry AP, Homes P, Hibbs M, Theobald AJ, Spitzfaden C, Bax BD Acta Crystallogr F Struct Biol Commun 71 1242-6 (2015)

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