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Volume 24, Issue 24
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Background

This study investigates the potential of eleven 1-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in infections.

Methods

A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders.

Results

Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors’ development.

Conclusion

These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against infections.

© 2024 Bentham Science Publishers
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2024-10-01
2025-01-22

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References

  1. BrinkacL. VoorhiesA. GomezA. NelsonK.E. The threat of antimicrobial resistance on the human microbiome.Microb. Ecol.20177441001100810.1007/s00248‑017‑0985‑z28492988
     [Google Scholar]
  2. BlaserM.J. Antibiotic use and its consequences for the normal microbiome.Science2016352628554454510.1126/science.aad935827126037
     [Google Scholar]
  3. ZhangQ.Q. YingG.G. PanC.G. LiuY.S. ZhaoJ.L. Comprehensive evaluation of antibiotics emission and fate in the river basins of China: Source analysis, multimedia modeling, and linkage to bacterial resistance.Environ. Sci. Technol.201549116772678210.1021/acs.est.5b0072925961663
     [Google Scholar]
  4. Centres for Disease Control and PreventionAntimicrobial resistance & patient safety portal.2024Available From: https://arpsp.cdc.gov/profile/antibiotic-resistance/mdr-pseudomonas-aeruginosa
  5. AndersonL. CloseG.L. KonopinskiM. RydingsD. MilsomJ. HamblyC. SpeakmanJ.R. DrustB. MortonJ.P. Case Study: Muscle atrophy, hypertrophy, and energy expenditure of a premier league soccer player during rehabilitation from anterior cruciate ligament injury.Int. J. Sport Nutr. Exerc. Metab.201929555956610.1123/ijsnem.2018‑039131034244
     [Google Scholar]
  6. DadgostarP. Antimicrobial resistance: Implications and costs.Infect. Drug Resist.2019123903391010.2147/IDR.S23461031908502
     [Google Scholar]
  7. ÅrdalC. BaraldiE. TheuretzbacherU. OuttersonK. PlahteJ. CiabuschiF. RøttingenJ.A. Insights into early stage of antibiotic development in small- and medium-sized enterprises: A survey of targets, costs, and durations.J. Pharm. Policy Pract.2018111810.1186/s40545‑018‑0135‑029632669
     [Google Scholar]
  8. JacksonN. CzaplewskiL. PiddockL.J.V. Discovery and development of new antibacterial drugs: Learning from experience?J. Antimicrob. Chemother.20187361452145910.1093/jac/dky01929438542
     [Google Scholar]
  9. MiethkeM. PieroniM. WeberT. BrönstrupM. HammannP. HalbyL. ArimondoP.B. GlaserP. AigleB. BodeH.B. MoreiraR. LiY. LuzhetskyyA. MedemaM.H. PernodetJ.L. StadlerM. TormoJ.R. GenilloudO. TrumanA.W. WeissmanK.J. TakanoE. SabatiniS. StegmannE. Brötz-OesterheltH. WohllebenW. SeemannM. EmptingM. HirschA.K.H. LoretzB. LehrC.M. TitzA. HerrmannJ. JaegerT. AltS. HesterkampT. WinterhalterM. SchieferA. PfarrK. HoeraufA. GrazH. GrazM. LindvallM. RamurthyS. KarlénA. van DongenM. PetkovicH. KellerA. PeyraneF. DonadioS. FraisseL. PiddockL.J.V. GilbertI.H. MoserH.E. MüllerR. Towards the sustainable discovery and development of new antibiotics.Nat. Rev. Chem.202151072674910.1038/s41570‑021‑00313‑1
     [Google Scholar]
  10. MauraD. BallokA.E. RahmeL.G. Considerations and caveats in anti-virulence drug development.Curr. Opin. Microbiol.201633414610.1016/j.mib.2016.06.00127318551
     [Google Scholar]
  11. KaliaV.C. Quorum sensing inhibitors: An overview.Biotechnol. Adv.201331222424510.1016/j.biotechadv.2012.10.00423142623
     [Google Scholar]
  12. PrazdnovaE.V. GorovtsovA.V. VasilchenkoN.G. KulikovM.P. StatsenkoV.N. BogdanovaA.A. RefeldA.G. BrislavskiyY.A. ChistyakovV.A. ChikindasM.L. Quorum-sensing inhibition by gram-positive bacteria.Microorganisms.202210235010.3390/microorganisms10020350
     [Google Scholar]
  13. QinS. XiaoW. ZhouC. PuQ. DengX. LanL. LiangH. SongX. WuM. Pseudomonas aeruginosa: Pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics.Signal Transduct. Target. Ther.20227119910.1038/s41392‑022‑01056‑135752612
     [Google Scholar]
  14. HuangH. ShaoX. XieY. WangT. ZhangY. WangX. DengX. An integrated genomic regulatory network of virulence-related transcriptional factors in Pseudomonas aeruginosa.Nat. Commun.2019101293110.1038/s41467‑019‑10778‑w31270321
     [Google Scholar]
  15. RadaB. LetoT.L. Pyocyanin effects on respiratory epithelium: Relevance in Pseudomonas aeruginosa airway infections.Trends Microbiol.2013212738110.1016/j.tim.2012.10.00423140890
     [Google Scholar]
  16. RamosI. DietrichL.E.P. Price-WhelanA. NewmanD.K. Phenazines affect biofilm formation by Pseudomonas aeruginosa in similar ways at various scales.Res. Microbiol.2010161318719110.1016/j.resmic.2010.01.00320123017
     [Google Scholar]
  17. HigginsS. HeebS. RampioniG. FletcherM.P. WilliamsP. CámaraM. Differential regulation of the phenazine biosynthetic operons by quorum sensing in Pseudomonas aeruginosa PAO1-N.Front. Cell. Infect. Microbiol.2018825210.3389/fcimb.2018.0025230083519
     [Google Scholar]
  18. JayaseelanS. RamaswamyD. DharmarajS. Pyocyanin: Production, applications, challenges and new insights.World J. Microbiol. Biotechnol.20143041159116810.1007/s11274‑013‑1552‑524214679
     [Google Scholar]
  19. da S M ForeziL. FroesT.Q. CardosoM.F.C. de Oliveira MacielC.A. NicastroG.G. BaldiniR.L. CostaD.C.S. FerreiraV.F. CastilhoM.S. de C da SilvaF. Synthesis and biological evaluation of coumarins derivatives as potential inhibitors of the production of pseudomonas aeruginosa virulence factor pyocyanin.Curr. Top. Med. Chem.201818214915610.2174/156802661866618032912270429595112
     [Google Scholar]
  20. FroesT.Q. GuidoR.V.C. MetwallyK. CastilhoM.S. A novel scaffold to fight Pseudomonas aeruginosa pyocyanin production: Early steps to novel antivirulence drugs.Future Med. Chem.202012161489150310.4155/fmc‑2019‑035132772556
     [Google Scholar]
  21. NitulescuG. MarginaD. ZanfirescuA. OlaruO.T. NitulescuG.M. Targeting bacterial sortases in search of anti-virulence therapies with low risk of resistance development.Pharmaceuticals (Basel)202114541510.3390/ph1405041533946434
     [Google Scholar]
  22. FroesT.Q. ChavesB.T. MendesM.S. XimenesR.M. da SilvaI.M. da SilvaP.B.G. de AlbuquerqueJ.F.C. CastilhoM.S. Synthesis and biological evaluation of thiazolidinedione derivatives with high ligand efficiency to P. aeruginosa PhzS.J. Enzyme Inhib. Med. Chem.20213611217122910.1080/14756366.2021.193116534080514
     [Google Scholar]
  23. FroesT.Q. BaldiniR.L. VajdaS. CastilhoM.S. Structure-based druggability assessment of anti-virulence targets from Pseudomonas aeruginosa.Curr. Protein Pept. Sci.201920121189120310.2174/138920372066619041712075831038064
     [Google Scholar]
  24. ParsonsJ.F. GreenhagenB.T. ShiK. CalabreseK. RobinsonH. LadnerJ.E. Structural and functional analysis of the pyocyanin biosynthetic protein PhzM from Pseudomonas aeruginosa .Biochemistry20074671821182810.1021/bi602440317253782
     [Google Scholar]
  25. GrøftehaugeM.K. HajizadehN.R. SwannM.J. PohlE. Protein–ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI).Acta Crystallogr. D Biol. Crystallogr.2015711364410.1107/S139900471401661725615858
     [Google Scholar]
  26. BaiN. RoderH. DicksonA. KaranicolasJ. Isothermal analysis of thermofluor data can readily provide quantitative binding affinities.Sci. Rep.201991265010.1038/s41598‑018‑37072‑x30804351
     [Google Scholar]
  27. TietzeL.F. SingidiR.R. GerickeK.M. Total synthesis of the proposed structure of the anthrapyran metabolite delta-indomycinone.Chemistry200713359939994710.1002/chem.20070082317886848
     [Google Scholar]
  28. PerezA.L. LamoureuxG. HerreraA. Synthesis of iodinated naphthoquinones using morpholine-iodine complex.Synth. Commun.200434183389339710.1081/SCC‑200030621
     [Google Scholar]
  29. SharmaJ. SinghP.K. SinghK.P. KhannaR.N. Iodination of Naphthoquinones and Coumarin Catalyzed by Ceric Ammonium and Mercuric Nitrates.Org. Prep. Proced. Int.1995271848610.1080/00304949509458181
     [Google Scholar]
  30. BoechatN. FerreiraV.F. FerreiraS.B. FerreiraM.L.G. da SilvaF.C. BastosM.M. CostaM.S. LourençoM.C.S. PintoA.C. KrettliA.U. AguiarA.C. TeixeiraB.M. da SilvaN.V. MartinsP.R.C. BezerraF.A.F.M. CamiloA.L.S. da SilvaG.P. CostaC.C.P. Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain.J. Med. Chem.201154175988599910.1021/jm200362421776985
     [Google Scholar]
  31. da SilvaI.F. MartinsP.R.C. da Silvae.g. FerreiraS.B. FerreiraV.F. da CostaK.R.C. de VasconcellosM.C. LimaE.S. da SilvaF.C. Synthesis of 1H-1,2,3-triazoles and study of their antifungal and cytotoxicity activities.Med. Chem.2013981085109010.2174/157340641130908001023432315
     [Google Scholar]
  32. CostaD.C.S. A stereoselective, base-free, palladium-catalyzed heck coupling between 3-halo-1,4-naphthoquinones and vinyl-1h-1,2,3-triazoles.ChemistrySelect2022724
     [Google Scholar]
  33. HansfordG.S. HollimanF.G. HerbertR.B. Pigments of Pseudomonas species. Part IV. in vitro and in vivo Conversion of 5-methylphenazinium-1-carboxylate into aeruginosin A.J. Chem. Soc., Perkin Trans. 11972110310510.1039/p197200001034626193
     [Google Scholar]
  34. SantosS.P. BandeirasT.M. PintoA.F. TeixeiraM. CarrondoM.A. RomãoC.V. Thermofluor-based optimization strategy for the stabilization and crystallization of Campylobacter jejuni desulforubrerythrin.Protein Expr. Purif.201281219320010.1016/j.pep.2011.10.00122051151
     [Google Scholar]
  35. WuT. HornsbyM. ZhuL. YuJ.C. ShokatK.M. GestwickiJ.E. Protocol for performing and optimizing differential scanning fluorimetry experiments.STAR Protocols20234410268810.1016/j.xpro.2023.10268837943662
     [Google Scholar]
  36. KopraK. ValtonenS. MahranR. KappJ.N. HassanN. GilletteW. DennisB. LiL. WestoverK.D. PlückthunA. HärmäH. Thermal shift assay for small GTPase stability screening: Evaluation and suitability.Int. J. Mol. Sci.20222313709510.3390/ijms2313709535806100
     [Google Scholar]
  37. RedheadM. SatchellR. MorkūnaitėV. SwiftD. PetrauskasV. GoldingE. OnionsS. MatulisD. UnittJ. A combinatorial biophysical approach; FTSA and SPR for identifying small molecule ligands and PAINs.Anal. Biochem.2015479637310.1016/j.ab.2015.03.01325837771
     [Google Scholar]
  38. HoldgateG.A. AndersonM. EdfeldtF. GeschwindnerS. Affinity-based, biophysical methods to detect and analyze ligand binding to recombinant proteins: Matching high information content with high throughput.J. Struct. Biol.2010172114215710.1016/j.jsb.2010.06.02420609391
     [Google Scholar]
  39. LeiteF.H.A. SantiagoP.B.G.S. FroesT.Q. da Silva FilhoJ. da SilvaS.G. XimenesR.M. de FariaA.R. BrondaniD.J. de AlbuquerqueJ.F.C. CastilhoM.S. Structure-guided discovery of thiazolidine-2,4-dione derivatives as a novel class of Leishmania major pteridine reductase 1 inhibitors.Eur. J. Med. Chem.201612363964810.1016/j.ejmech.2016.07.06027517809
     [Google Scholar]
  40. VivoliM. NovakH.R. LittlechildJ.A. HarmerN.J. Determination of protein-ligand interactions using differential scanning fluorimetry.J. Vis. Exp.2014915180925285605
     [Google Scholar]
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1H-1,2,3-triazol-1,4-naphthoquinone Derivatives: Novel Inhibitors Targeting Pyocyanin Biosynthesis for P. Aeruginosa Infection Treatment Advances
Curr. Top. Med. Chem. 24, 2161 (2024); https://doi.org/10.2174/0115680266327024240726111230
/content/journals/ctmc/10.2174/0115680266327024240726111230
/content/journals/ctmc/10.2174/0115680266327024240726111230
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  • Article Type:     Research Article
Keyword(s): Pyocyanin; 1H-1,2,3-Triazol-1,4-naphthoquinone; Novel inhibitors; P. aeruginosa; Spectroscopic analyses, PhzM binders

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