Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Research Article

Design and Biological Evaluation of Cephalosporin Based Metallo-β-lactamase (MBL) Inhibitors#

Author(s): Shaan Patel*, Pradip Jadav*, Rajesh Bahekar, Kumargurubaran Nagaswamy, Kasinath Viswanathan, Purvi Vyas, Poonam Giri, S. Sachchidanand and Mukul Jain

Volume 21, Issue 16, 2024

Published on: 24 April, 2024

Page: [3506 - 3514] Pages: 9

DOI: 10.2174/0115701808287192240415062148

Price: $65

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 Veronaintegron encoded metallo-β-lactamase 2 (VIM-2) bacterial enzyme through hydrolytic cleavage mechanism. A total of 6 (4a-e and 6f) New Chemical Entities (NCE’s) were prepared, characterized and subjected for in vitro study.

Conclusion: Among tested NCE’s, 4c showed potent MBL inhibitory activity against the VIM-2 enzyme.

« Previous Next »
[1]
Bush, K.; Macielag, M.J. New β-lactam antibiotics and β-lactamase inhibitors. Expert Opin. Ther. Pat., 2010, 20(10), 1277-1293.
[http://dx.doi.org/10.1517/13543776.2010.515588] [PMID: 20839927]
[2]
Tipper, D.J. Mode of action of β-lactam antibiotics. Pharmacol. Ther., 1985, 27(1), 1-35.
[http://dx.doi.org/10.1016/0163-7258(85)90062-2] [PMID: 3889939]
[3]
Spratt, B.G.; Cromie, K.D. Penicillin-binding proteins of gram-negative bacteria. Clin. Infect. Dis., 1988, 10(4), 699-711.
[http://dx.doi.org/10.1093/clinids/10.4.699] [PMID: 3055170]
[4]
Kong, K.F.; Schneper, L.; Mathee, K. Beta‐lactam antibiotics: From antibiosis to resistance and bacteriology. Acta Pathol. Microbiol. Scand. Suppl., 2010, 118(1), 1-36.
[http://dx.doi.org/10.1111/j.1600-0463.2009.02563.x] [PMID: 20041868]
[5]
Årdal, C.; Balasegaram, M.; Laxminarayan, R.; McAdams, D.; Outterson, K.; Rex, J.H.; Sumpradit, N. Antibiotic development — economic, regulatory and societal challenges. Nat. Rev. Microbiol., 2020, 18(5), 267-274.
[http://dx.doi.org/10.1038/s41579-019-0293-3] [PMID: 31745330]
[6]
Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol., 2015, 13(1), 42-51.
[http://dx.doi.org/10.1038/nrmicro3380] [PMID: 25435309]
[7]
Crowder, M.W.; Aitha, M.; Bonomo, R.A.; Lisa, M-N.; Moreno, D.M.; Vila, A.J.; Llarrull, L.I.; Palacios, A.R.; Tierney, D.L.; González, M.M. Spencer. J. Nat. Commun., 2017, 8, 1-11.
[http://dx.doi.org/10.1038/s41467-016-0009-6] [PMID: 28232747]
[8]
Sun, Z.; Hu, L.; Sankaran, B.; Prasad, B.V.V.; Palzkill, T. Differential active site requirements for NDM-1 β-lactamase hydrolysis of carbapenem versus penicillin and cephalosporin antibiotics. Nat. Commun., 2018, 9(1), 4524.
[http://dx.doi.org/10.1038/s41467-018-06839-1] [PMID: 30375382]
[9]
Tehrani, K.H.M.E.; Martin, N.I. β-lactam/β-lactamase inhibitor combinations: An update. MedChemComm, 2018, 9(9), 1439-1456.
[http://dx.doi.org/10.1039/C8MD00342D] [PMID: 30288219]
[10]
Dalal, V.; Dhankhar, P.; Singh, V.; Singh, V.; Rakhaminov, G.; Golemi-Kotra, D.; Kumar, P. Structure-based identification of potential drugs against FmtA of Staphylococcus aureus: Virtual screening, molecular dynamics, MM-GBSA, and QM/MM. Protein J., 2021, 40(2), 148-165.
[http://dx.doi.org/10.1007/s10930-020-09953-6] [PMID: 33421024]
[11]
Singh, V.; Dhankhar, P.; Dalal, V.; Tomar, S.; Golemi-Kotra, D.; Kumar, P. Drug-repurposing approach to combat Staphylococcus aureus: Biomolecular and binding interaction study. ACS Omega, 2022, 7(43), 38448-38458.
[http://dx.doi.org/10.1021/acsomega.2c03671] [PMID: 36340146]
[12]
Ju, L.C.; Cheng, Z.; Fast, W.; Bonomo, R.A.; Crowder, M.W. The continuing challenge of Metallo-β-Lactamase inhibition: Mechanism matters. Trends Pharmacol. Sci., 2018, 39(7), 635-647.
[http://dx.doi.org/10.1016/j.tips.2018.03.007] [PMID: 29680579]
[13]
Rotondo, C.M.; Wright, G.D. Inhibitors of metallo-β-lactamases. Curr. Opin. Microbiol., 2017, 39, 96-105.
[http://dx.doi.org/10.1016/j.mib.2017.10.026] [PMID: 29154026]
[14]
Somboro, A.M.; Osei Sekyere, J.; Amoako, D.G.; Essack, S.Y.; Bester, L.A. Diversity and Proliferation of Metallo-β-Lactamases: A Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors. Appl. Environ. Microbiol., 2018, 84(18), e00698-e18.
[http://dx.doi.org/10.1128/AEM.00698-18]
[15]
Fisher, J.F.; Meroueh, S.O.; Mobashery, S. Bacterial resistance to beta-lactam antibiotics: Compelling opportunism, compelling opportunity. Chem. Rev., 2005, 105(2), 395-424.
[http://dx.doi.org/10.1021/cr030102i] [PMID: 15700950]
[16]
Singh, V.; Dhankhar, P.; Dalal, V.; Tomar, S.; Kumar, P. In-silico functional and structural annotation of hypothetical protein from Klebsiella pneumonia: A potential drug target. J. Mol. Graph. Model., 2022, 116, 108262.
[http://dx.doi.org/10.1016/j.jmgm.2022.108262] [PMID: 35839717]
[17]
Bush, K. Alarming β-lactamase-mediated resistance in multidrug-resistant Enterobacteriaceae. Curr. Opin. Microbiol., 2010, 13(5), 558-564.
[http://dx.doi.org/10.1016/j.mib.2010.09.006] [PMID: 20920882]
[18]
Wang, Z.; Fast, W.; Valentine, A.M.; Benkovic, S.J. Metallo-β-lactamase: structure and mechanism. Curr. Opin. Chem. Biol., 1999, 3, 614-622.
[http://dx.doi.org/10.1016/S1367-5931(99)00017-4] [PMID: 10508665]
[19]
Buynak, J.D. β-Lactamase inhibitors: A review of the patent literature (2010 – 2013). Expert Opin. Ther. Pat., 2013, 23(11), 1469-1481.
[http://dx.doi.org/10.1517/13543776.2013.831071] [PMID: 23967802]
[20]
Leal, S.M.; Amado, D.F.; Kouznetsov, V.V.; Escobar, P. In vitro antileishmanial, trypanocidal, and mammalian cell activities of diverse n,n′ -dihetaryl substituted diamines and related compounds. Sci. Pharm., 2013, 81(1), 43-55.
[http://dx.doi.org/10.3797/scipharm.1205-14] [PMID: 23641328]
[21]
Li, G.B.; Abboud, M.I.; Brem, J.; Someya, H.; Lohans, C.T.; Yang, S.Y.; Spencer, J.; Wareham, D.W.; McDonough, M.A.; Schofield, C.J. NMR-filtered virtual screening leads to non-metal chelating metallo-β-lactamase inhibitors. Chem. Sci. (Camb.), 2017, 8(2), 928-937.
[http://dx.doi.org/10.1039/C6SC04524C]
[22]
Tehrani, K.H.M.E.; Fu, H.; Brechle, N.C.; Mashayekhi, V. 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.), 2020, 56, 3047-3049.
[http://dx.doi.org/10.1039/D0CC00356E] [PMID: 32048688]
[23]
King, A.M.; Reid-Yu, S.A.; Wang, W.; King, D.T.; De Pascale, G.; Strynadka, N.C.; Walsh, T.R.; Coombes, B.K.; Wright, G.D. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance. Nature, 2014, 510(7506), 503-506.
[http://dx.doi.org/10.1038/nature13445] [PMID: 24965651]
[24]
Chen, A.Y.; Thomas, P.W.; Stewart, A.C.; Bergstrom, A.; Cheng, Z.; Miller, C.; Bethel, C.R.; Marshall, S.H.; Credille, C.V.; Riley, C.L.; Page, R.C.; Bonomo, R.A.; Crowder, M.W.; Tierney, D.L.; Fast, W.; Cohen, S.M. Dipicolinic acid derivatives as inhibitors of new delhi Metallo-β-lactamase-1. J. Med. Chem., 2017, 60(17), 7267-7283.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00407] [PMID: 28809565]
[25]
Perez, C.; Li, J.; Parlati, F.; Rouffet, M.; Ma, Y.; Mackinnon, A.L.; Chou, T.F.; Deshaies, R.J.; Cohen, S.M. Discovery of an inhibitor of the proteasome subunit Rpn11. J. Med. Chem., 2017, 60(4), 1343-1361.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01379] [PMID: 28191850]
[26]
Li, J.; Yakushi, T.; Parlati, F.; Mackinnon, A.L.; Perez, C.; Ma, Y.; Carter, K.P.; Colayco, S.; Magnuson, G.; Brown, B.; Nguyen, K.; Vasile, S.; Suyama, E.; Smith, L.H.; Sergienko, E.; Pinkerton, A.B.; Chung, T.D.Y.; Palmer, A.E.; Pass, I.; Hess, S.; Cohen, S.M.; Deshaies, R.J. Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11. Nat. Chem. Biol., 2017, 13(5), 486-493.
[http://dx.doi.org/10.1038/nchembio.2326] [PMID: 28244987]
[27]
Hameed, D.S.; Sapmaz, A.; Burggraaff, L.; Amore, A.; Slingerland, C.J.; van Westen, G.J.P.; Ovaa, H. Development of Ubiquitin‐Based Probe for Metalloprotease Deubiquitinases. Angew. Chem. Int. Ed., 2019, 58(41), 14477-14482.
[http://dx.doi.org/10.1002/anie.201906790]
[28]
van Haren, M.J.; Tehrani, K.H.M.E.; Kotsogianni, I.; Wade, N.; Brüchle, N.C.; Mashayekhi, V.; Martin, N.I. Cephalosporin prodrug inhibitors overcome Metallo‐β‐Lactamase driven antibiotic resistance. Chemistry, 2021, 27(11), 3806-3811.
[http://dx.doi.org/10.1002/chem.202004694] [PMID: 33237604]
[29]
Tehrani, K.H.M.E.; Martin, N.I. Thiol-containing metallo-β-Lactamase inhibitors resensitize resistant gram-negative bacteria to meropenem. ACS Infect. Dis., 2017, 3(10), 711-717.
[http://dx.doi.org/10.1021/acsinfecdis.7b00094] [PMID: 28820574]
[30]
Cain, R.; Schofield, C.J.; Brem, J.; Fishwick, C.W.G.; van Berkel, S.S.; Owens, R.J.; Spencer, J.; Rydzik, A.M.; Salimraj, R.; Verma, A. J. Med. Chem., 2013, 56, 6945-6953.
[http://dx.doi.org/10.1021/jm400769b] [PMID: 23898798]
[31]
Evans, L.E.; Krishna, A.; Ma, Y.; Webb, T.E.; Marshall, D.C.; Tooke, C.L.; Spencer, J.; Clarke, T.B.; Armstrong, A.; Edwards, A.M. Exploitation of antibiotic resistance as a novel drug target: Development of a β-Lactamase-activated antibacterial prodrug. J. Med. Chem., 2019, 62(9), 4411-4425.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01923] [PMID: 31009558]
[32]
Jackson, A.C.; Zaengle-Barone, J.M.; Puccio, E.A.; Franz, K.J. A cephalosporin prochelator inhibits New Delhi Metallo-β-lactamase 1 without removing zinc. ACS Infect. Dis., 2020, 6(5), 1264-1272.
[http://dx.doi.org/10.1021/acsinfecdis.0c00083] [PMID: 32298084]
[33]
Corey, E.J. Robert Robinson Lecture. Retrosynthetic thinking-Essentials and Examples Chem. Soc. Rev., 1988, 17, 111-133.
[http://dx.doi.org/10.1039/CS9881700111]
[34]
Sahoo, P. K; Sundaravadivelan, S.; Surulichamy, S.K.; Upadhyay, M. Process for preparation of cefepime dihydrochloride monohydrate. WO2011121389A1, 2010.
[35]
Hughes, D.L. Patent Review of Manufacturing Routes to Fifth-Generation Cephalosporin Drugs. Part 2, Ceftaroline Fosamil and Ceftobiprole Medocaril. Org. Process Res. Dev., 2017, 21(6), 800-815.
[http://dx.doi.org/10.1021/acs.oprd.7b00143]
[36]
Abagyan, R.; Totrov, M.; Kuznetsov, D. ICM—A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation. J. Comput. Chem., 1994, 15(5), 488-506.
[http://dx.doi.org/10.1002/jcc.540150503]
[37]
Lucic, A.; Hinchliffe, P.; Malla, T.R.; Tooke, C.L.; Brem, J.; Calvopiña, K.; Lohans, C.T.; Rabe, P.; McDonough, M.A.; Armistead, T.; Orville, A.M.; Spencer, J.; Schofield, C.J. Faropenem reacts with serine and metallo-β-lactamases to give multiple products. Eur. J. Med. Chem., 2021, 215, 113257.
[http://dx.doi.org/10.1016/j.ejmech.2021.113257] [PMID: 33618159]
[38]
Neves, M.A.C.; Totrov, M.; Abagyan, R. Docking and scoring with ICM: The benchmarking results and strategies for improvement. J. Comput. Aided Mol. Des., 2012, 26(6), 675-686.
[http://dx.doi.org/10.1007/s10822-012-9547-0] [PMID: 22569591]
[39]
Liu, B.; Trout, R.E.L.; Chu, G.H.; McGarry, D.; Jackson, R.W.; Hamrick, J.C.; Daigle, D.M.; Cusick, S.M.; Pozzi, C.; De Luca, F.; Benvenuti, M.; Mangani, S.; Docquier, J.D.; Weiss, W.J.; Pevear, D.C.; Xerri, L.; Burns, C.J. Discovery of Taniborbactam (VNRX-5133): A Broad-Spectrum Serine- and Metallo-β-lactamase Inhibitor for Carbapenem-Resistant Bacterial Infections. J. Med. Chem., 2020, 63(6), 2789-2801.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01518] [PMID: 31765155]
[40]
Su, M.; Yang, Q.; Du, Y.; Feng, G. Comparative assessment of scoring functions: The CASF-2016 update. J. Chem. Inf. Model., 2019, 59, 895-913.
[http://dx.doi.org/10.1021/acs.jcim.8b00545] [PMID: 30481020]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy