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Volume 21, Issue 16
  • ISSN: 1570-1808
  • E-ISSN: 1875-628X

Abstract

Background

Prevalence of microbial resistance due to Metallo-β-lactamase (MBL) enzyme pose a serious threat to human life. MBLs depend on active site zinc for their hydrolytic activity; hence, the investigation of zinc chelators emerged as an attractive strategy for the development of potent MBL inhibitors.

Methods

To prove that such chelators selectively target MBLs, in the present investigation, novel cephalosporins based MBL inhibitors (Cef-MBLi) were designed as a conjugate of cephalosporins with a potent zinc binder 8-thioquinoline (8-TQ).

Results

Cef-MBLi showed site specific release of conjugate only in the presence of a Verona-integron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage mechanism. A total of 6 ( and ) New Chemical Entities (NCE’s) were prepared, characterized and subjected for study.

Conclusion

Among tested NCE’s, showed potent MBL inhibitory activity against the VIM-2 enzyme.

© 2024 Bentham Science Publishers
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2024-04-24
2025-05-30

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References

  1. BushK. MacielagM.J. New β-lactam antibiotics and β-lactamase inhibitors.Expert Opin. Ther. Pat.201020101277129310.1517/13543776.2010.515588 20839927
     [Google Scholar]
  2. TipperD.J. Mode of action of β-lactam antibiotics.Pharmacol. Ther.198527113510.1016/0163‑7258(85)90062‑2 3889939
     [Google Scholar]
  3. SprattB.G. CromieK.D. Penicillin-binding proteins of gram-negative bacteria.Clin. Infect. Dis.198810469971110.1093/clinids/10.4.699 3055170
     [Google Scholar]
  4. KongK.F. SchneperL. MatheeK. Beta‐lactam antibiotics: From antibiosis to resistance and bacteriology.Acta Pathol. Microbiol. Scand. Suppl.2010118113610.1111/j.1600‑0463.2009.02563.x 20041868
     [Google Scholar]
  5. ÅrdalC. BalasegaramM. LaxminarayanR. McAdamsD. OuttersonK. RexJ.H. SumpraditN. Antibiotic development — economic, regulatory and societal challenges.Nat. Rev. Microbiol.202018526727410.1038/s41579‑019‑0293‑3 31745330
     [Google Scholar]
  6. BlairJ.M.A. WebberM.A. BaylayA.J. OgboluD.O. PiddockL.J.V. Molecular mechanisms of antibiotic resistance.Nat. Rev. Microbiol.2015131425110.1038/nrmicro3380 25435309
     [Google Scholar]
  7. CrowderM.W. AithaM. BonomoR.A. LisaM-N. MorenoD.M. VilaA.J. LlarrullL.I. PalaciosA.R. TierneyD.L. GonzálezM.M. Spencer.J. Nat. Commun.2017811110.1038/s41467‑016‑0009‑6 28232747
     [Google Scholar]
  8. SunZ. HuL. SankaranB. PrasadB.V.V. PalzkillT. Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics.Nat. Commun.201891452410.1038/s41467‑018‑06839‑1 30375382
     [Google Scholar]
  9. TehraniK.H.M.E. MartinN.I. β-lactam/β-lactamase inhibitor combinations: An update.MedChemComm2018991439145610.1039/C8MD00342D 30288219
     [Google Scholar]
  10. DalalV. DhankharP. SinghV. SinghV. RakhaminovG. Golemi-KotraD. KumarP. Structure-based identification of potential drugs against FmtA of Staphylococcus aureus: Virtual screening, molecular dynamics, MM-GBSA, and QM/MM.Protein J.202140214816510.1007/s10930‑020‑09953‑6 33421024
     [Google Scholar]
  11. SinghV. DhankharP. DalalV. TomarS. Golemi-KotraD. KumarP. Drug-repurposing approach to combat Staphylococcus aureus: Biomolecular and binding interaction study.ACS Omega2022743384483845810.1021/acsomega.2c03671 36340146
     [Google Scholar]
  12. JuL.C. ChengZ. FastW. BonomoR.A. CrowderM.W. The continuing challenge of Metallo-β-Lactamase inhibition: Mechanism matters.Trends Pharmacol. Sci.201839763564710.1016/j.tips.2018.03.007 29680579
     [Google Scholar]
  13. RotondoC.M. WrightG.D. Inhibitors of metallo-β-lactamases.Curr. Opin. Microbiol.2017399610510.1016/j.mib.2017.10.026 29154026
     [Google Scholar]
  14. SomboroA.M. Osei SekyereJ. AmoakoD.G. EssackS.Y. BesterL.A. Diversity and Proliferation of Metallo-β-Lactamases: A Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors.Appl. Environ. Microbiol.20188418e00698e1810.1128/AEM.00698‑18
     [Google Scholar]
  15. FisherJ.F. MerouehS.O. MobasheryS. Bacterial resistance to beta-lactam antibiotics: Compelling opportunism, compelling opportunity.Chem. Rev.2005105239542410.1021/cr030102i 15700950
     [Google Scholar]
  16. SinghV. DhankharP. DalalV. TomarS. KumarP. In-silico functional and structural annotation of hypothetical protein from Klebsiella pneumonia: A potential drug target.J. Mol. Graph. Model.202211610826210.1016/j.jmgm.2022.108262 35839717
     [Google Scholar]
  17. BushK. Alarming β-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae.Curr. Opin. Microbiol.201013555856410.1016/j.mib.2010.09.006 20920882
     [Google Scholar]
  18. WangZ. FastW. ValentineA.M. BenkovicS.J. Metallo-β-lactamase: structure and mechanism.Curr. Opin. Chem. Biol.1999361462210.1016/S1367‑5931(99)00017‑4 10508665
     [Google Scholar]
  19. BuynakJ.D. β-Lactamase inhibitors: A review of the patent literature (2010 – 2013).Expert Opin. Ther. Pat.201323111469148110.1517/13543776.2013.831071 23967802
     [Google Scholar]
  20. LealS.M. AmadoD.F. KouznetsovV.V. EscobarP. In vitro antileishmanial, trypanocidal, and mammalian cell activities of diverse n,n′ -dihetaryl substituted diamines and related compounds.Sci. Pharm.2013811435510.3797/scipharm.1205‑14 23641328
     [Google Scholar]
  21. LiG.B. AbboudM.I. BremJ. SomeyaH. LohansC.T. YangS.Y. SpencerJ. WarehamD.W. McDonoughM.A. SchofieldC.J. NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors.Chem. Sci. (Camb.)20178292893710.1039/C6SC04524C
     [Google Scholar]
  22. TehraniK.H.M.E. FuH. BrechleN.C. MashayekhiV. Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N′-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1.Chem. Commun. (Camb.)2020563047304910.1039/D0CC00356E 32048688
     [Google Scholar]
  23. KingA.M. Reid-YuS.A. WangW. KingD.T. De PascaleG. StrynadkaN.C. WalshT.R. CoombesB.K. WrightG.D. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance.Nature2014510750650350610.1038/nature13445 24965651
     [Google Scholar]
  24. ChenA.Y. ThomasP.W. StewartA.C. BergstromA. ChengZ. MillerC. BethelC.R. MarshallS.H. CredilleC.V. RileyC.L. PageR.C. BonomoR.A. CrowderM.W. TierneyD.L. FastW. CohenS.M. Dipicolinic acid derivatives as inhibitors of new delhi Metallo-β-lactamase-1.J. Med. Chem.201760177267728310.1021/acs.jmedchem.7b00407 28809565
     [Google Scholar]
  25. PerezC. LiJ. ParlatiF. RouffetM. MaY. MackinnonA.L. ChouT.F. DeshaiesR.J. CohenS.M. Discovery of an inhibitor of the proteasome subunit Rpn11.J. Med. Chem.20176041343136110.1021/acs.jmedchem.6b01379 28191850
     [Google Scholar]
  26. LiJ. YakushiT. ParlatiF. MackinnonA.L. PerezC. MaY. CarterK.P. ColaycoS. MagnusonG. BrownB. NguyenK. VasileS. SuyamaE. SmithL.H. SergienkoE. PinkertonA.B. ChungT.D.Y. PalmerA.E. PassI. HessS. CohenS.M. DeshaiesR.J. Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.Nat. Chem. Biol.201713548649310.1038/nchembio.2326 28244987
     [Google Scholar]
  27. HameedD.S. SapmazA. BurggraaffL. AmoreA. SlingerlandC.J. van WestenG.J.P. OvaaH. Development of Ubiquitin‐Based Probe for Metalloprotease Deubiquitinases.Angew. Chem. Int. Ed.20195841144771448210.1002/anie.201906790
     [Google Scholar]
  28. van HarenM.J. TehraniK.H.M.E. KotsogianniI. WadeN. BrüchleN.C. MashayekhiV. MartinN.I. Cephalosporin prodrug inhibitors overcome Metallo‐β‐Lactamase driven antibiotic resistance.Chemistry202127113806381110.1002/chem.202004694 33237604
     [Google Scholar]
  29. TehraniK.H.M.E. MartinN.I. Thiol-containing metallo-β-Lactamase inhibitors resensitize resistant gram-negative bacteria to meropenem.ACS Infect. Dis.201731071171710.1021/acsinfecdis.7b00094 28820574
     [Google Scholar]
  30. CainR. SchofieldC.J. BremJ. FishwickC.W.G. van BerkelS.S. OwensR.J. SpencerJ. RydzikA.M. SalimrajR. VermaA. J. Med. Chem.2013566945695310.1021/jm400769b 23898798
     [Google Scholar]
  31. EvansL.E. KrishnaA. MaY. WebbT.E. MarshallD.C. TookeC.L. SpencerJ. ClarkeT.B. ArmstrongA. EdwardsA.M. Exploitation of antibiotic resistance as a novel drug target: Development of a β-Lactamase-activated antibacterial prodrug.J. Med. Chem.20196294411442510.1021/acs.jmedchem.8b01923 31009558
     [Google Scholar]
  32. JacksonA.C. Zaengle-BaroneJ.M. PuccioE.A. FranzK.J. A cephalosporin prochelator inhibits New Delhi Metallo-β-lactamase 1 without removing zinc.ACS Infect. Dis.2020651264127210.1021/acsinfecdis.0c00083 32298084
     [Google Scholar]
  33. CoreyE.J. Robert Robinson Lecture. Retrosynthetic thinking-Essentials and Examples Chem.Soc. Rev.19881711113310.1039/CS9881700111
     [Google Scholar]
  34. SahooP. K SundaravadivelanS. SurulichamyS.K. UpadhyayM. Process for preparation of cefepime dihydrochloride monohydrate.WO2011121389A12010
  35. HughesD.L. Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 2, Ceftaroline Fosamil and Ceftobiprole Medocaril.Org. Process Res. Dev.201721680081510.1021/acs.oprd.7b00143
     [Google Scholar]
  36. AbagyanR. TotrovM. KuznetsovD. ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation.J. Comput. Chem.199415548850610.1002/jcc.540150503
     [Google Scholar]
  37. LucicA. HinchliffeP. MallaT.R. TookeC.L. BremJ. CalvopiñaK. LohansC.T. RabeP. McDonoughM.A. ArmisteadT. OrvilleA.M. SpencerJ. SchofieldC.J. Faropenem reacts with serine and metallo-β-lactamases to give multiple products.Eur. J. Med. Chem.202121511325710.1016/j.ejmech.2021.113257 33618159
     [Google Scholar]
  38. NevesM.A.C. TotrovM. AbagyanR. Docking and scoring with ICM: The benchmarking results and strategies for improvement.J. Comput. Aided Mol. Des.201226667568610.1007/s10822‑012‑9547‑0 22569591
     [Google Scholar]
  39. LiuB. TroutR.E.L. ChuG.H. McGarryD. JacksonR.W. HamrickJ.C. DaigleD.M. CusickS.M. PozziC. De LucaF. BenvenutiM. ManganiS. DocquierJ.D. WeissW.J. PevearD.C. XerriL. BurnsC.J. Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections.J. Med. Chem.20206362789280110.1021/acs.jmedchem.9b01518 31765155
     [Google Scholar]
  40. SuM. YangQ. DuY. FengG. Comparative assessment of scoring functions: The CASF-2016 update.J. Chem. Inf. Model.20195989591310.1021/acs.jcim.8b00545 30481020
     [Google Scholar]
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Design and Biological Evaluation of Cephalosporin based Metallo-β-lactamase (MBL) Inhibitors#
Letters in Drug Design & Discovery 21, 3506 (2024); https://doi.org/10.2174/0115701808287192240415062148
/content/journals/lddd/10.2174/0115701808287192240415062148
/content/journals/lddd/10.2174/0115701808287192240415062148
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Supplements

The supporting information (SI) available as a separate document, which contains further information about IR, NMR MS and HPLC spectral data of synthesized compounds. Supplementary material is available on the publisher's website along with the published article.

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  • Article Type:     Research Article
Keyword(s): 8-thioquinoline (8-TQ); Antibiotic (Abs); antibiotic resistance; cephalosporin based MBL inhibitors (Cef-MBLi); conjugates; enzyme inhibition; metallo-β-lactamase (MBL) enzymes

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