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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

N-(Sulfamoylbenzoyl)-L-proline Derivatives as Potential Non-β-lactam ESBL Inhibitors: Structure-Based Lead Identification, Medicinal Chemistry and Synergistic Antibacterial Activities

Author(s): Xinyu Liu, Shengjie Dong, Yuru Ma, Hu Xu, Hongxia Zhao* and Qingzhi Gao*

Volume 15, Issue 2, 2019

Page: [196 - 206] Pages: 11

DOI: 10.2174/1573406414666180816123232

Price: $65

Abstract

Background: There is an urgent need to develop novel inhibitors against clinically widespread extended-spectrum β-lactamases (ESBLs) to meet the challenges of the ever-evolving threat of antibiotic resistances. Most existing ESBL inhibitors sharing a common chemical feature of β-lactam ring in their molecule, this structural characteristic makes them intrinsically susceptible to enzymatic breakdown by the resistance mechanisms employed by the bacteria.

Objective: The aim of this study was to screen and discover novel lead compounds by using Lproline as initial scaffold to create a “non-sulfur, non-β-lactam” new chemotypes for potential ESBL inhibitors.

Methods: Structure-based molecular docking and virtual screening were employed in the novel inhibitor generation process for lead compound screening and SAR analysis. Evaluation of the ESBL inhibitory activity of the lead compounds was performed in combination with three of the most susceptible antibiotics: ceftazidime, meropenem and ampicillin, against thirteen ESBL enzymes including four new CTX-M harboring strains and four KPC-2 producing species.

Results: L-proline derived (S)-1-(2-sulfamoylbenzoyl)pyrrolidine-2-carboxylic acid (compound 6) as a “non-sulfur, non-β-lactam” and the most potential ESBL inhibitor was identified. Compound 6 possesses ideal anti-resistance activities by reducing MICs of ceftazidime, meropenem and ampicillin by 16-133, 32-133 and 67-267 fold respectiveily. The inhibitory mechanism of 6 with CTX-M, KPC-2 and penicillinase were proposed and probed with molecular docking analysis.

Conclusion: Given that the simple proline derivative but promising synergistic antibacterial properties of compound 6 augers well for further investigations into its in vivo efficacy.

Keywords: L-proline derivative, β-lactamase inhibitor, enzymes, structure-based virtual screening, molecular docking, antibiotics.

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[1]
Fisher, J.F.; Meroueh, S.O.; Mobashery, S. Bacterial resistance to beta-lactam antibiotics: compelling opportunism, compelling opportunity. Chem. Rev., 2005, 105, 395-424.
[2]
Bush, K.; Jacoby, G.A. Updated functional classification of beta-lactamases. Antimicrob. Agents Chemother., 2010, 54, 969-976.
[3]
Bush, K. The ABCD’s of β-lactamase nomenclature. J. Infect. Chemother., 2013, 19, 549-559.
[4]
Ehmann, D.E.; Jahic, H.; Ross, P.L.; Gu, R.F.; Hu, J.; Durand-Réville, T.F.; Lahiri, S.; Thresher, J.; Livchak, S.; Gao, N.; Palmer, T.; Walkup, G.K.; Fisher, S.L. Kinetics of avibactam inhibition against Class A, C, and D β-lactamases. J. Biol. Chem., 2013, 288, 27960-27971.
[5]
Klingler, F.M.; Wichelhaus, T.A.; Frank, D.; Cuesta-Bernal, J.; El-Delik, J.; Müller, H.F.; Sjuts, H.; Göttig, S.; Koenigs, A.; Pos, K.M.; Pogoryelov, D.; Proschak, E. Approved Drugs Containing Thiols as Inhibitors of Metallo-β-lactamases: Strategy To Combat Multidrug-Resistant Bacteria. J. Med. Chem., 2015, 58, 3626-3630.
[6]
Karsisiotis, A.I.; Damblon, C.F.; Roberts, G.C. A variety of roles for versatile zinc in metallo-β-lactamases. Metallomics, 2014, 6, 1181-1197.
[7]
Yang, Y.; Rasmussen, B.A.; Shlaes, D.M. Class A beta-lactamases--enzyme-inhibitor interactions and resistance. Pharmacol. Ther., 1999, 83, 141-151.
[8]
Zygmunt, D.J.; Stratton, C.W.; Kernodle, D.S. Characterization of four beta-lactamases produced by Staphylococcus aureus. Antimicrob. Agents Chemother., 1992, 36, 440-445.
[9]
Rossolini, G.M.; D’Andrea, M.M.; Mugnaioli, C. The spread of CTX-M-type extended-spectrum beta-lactamases. Clin. Microbiol. Infect., 2008, 14, 33-41.
[10]
Bonnet, R. Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes. Antimicrob. Agents Chemother., 2004, 48, 1-14.
[11]
Chen, Y.; Shoichet, B.; Bonnet, R. Structure, function, and inhibition along the reaction coordinate of CTX-M beta-lactamases. J. Am. Chem. Soc., 2005, 127, 5423-5434.
[12]
Bush, K.; Fisher, J.F. Epidemiological expansion, structural studies, and clinical challenges of new β-lactamases from gram-negative bacteria. Annu. Rev. Microbiol., 2011, 65, 455-478.
[13]
Stewart, N.K.; Smith, C.A.; Frase, H.; Black, D.J.; Vakulenko, S.B. Kinetic and structural requirements for carbapenemase activity in GES-type β-lactamases. Biochemistry, 2015, 54, 588-597.
[14]
Bradford, P.A. Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev., 2001, 14, 933-951.
[15]
Perez, F.; Endimiani, A.; Hujer, K.M.; Bonomo, R.A. The continuing challenge of ESBLs. Curr. Opin. Pharmacol., 2007, 7, 459-469.
[16]
Biondi, S.; Long, S.; Panunzio, M.; Qin, W.L. Current trends in β-lactam based β-lactamases inhibitors. Curr. Med. Chem., 2011, 18, 4223-4236.
[17]
Drawz, S.M.; Bonomo, R.A. Three decades of beta-lactamase inhibitors. Clin. Microbiol. Rev., 2010, 23, 160-201.
[18]
Nichols, D.A.; Jaishankar, P.; Larson, W.; Smith, E.; Liu, G.; Beyrouthy, R.; Bonnet, R.; Renslo, A.R.; Chen, Y. Structure-based design of potent and ligand-efficient inhibitors of CTX-M class A β-lactamase. J. Med. Chem., 2012, 55, 2163-2172.
[19]
Nichols, D.A.; Renslo, A.R.; Chen, Y. Fragment-based inhibitor discovery against β-lactamase. Future Med. Chem., 2014, 6, 413-427.
[20]
Tondi, D.; Venturelli, A.; Bonnet, R.; Pozzi, C.; Shoichet, B.K.; Costi, M.P. Targeting class A and C serine β-lactamases with a broad-spectrum boronic acid derivative. J. Med. Chem., 2014, 57, 5449-5458.
[21]
Hanson, N.D.; Sanders, C.C. Regulation of inducible AmpC beta-lactamase expression among Enterobacteriaceae. Curr. Pharm. Des., 1999, 5, 881-894.
[22]
Hu, M.; Chen, J.; Tran, D.; Zhu, Y.; Leonardo, G. The caco-2 cell monolayers as an intestinal metabolism model: metabolism of dipeptide Phe-Pro. J. Drug Target., 1994, 2, 79-89.
[23]
Li, N.; Xu, Y.; Xia, Q.; Bai, C.; Wang, T.; Wang, L.; He, D.; Xie, N.; Li, L.; Wang, J.; Zhou, H.G.; Xu, F.; Yang, C.; Zhang, Q.; Yin, Z.; Guo, Y.; Chen, Y. Simplified captopril analogues as NDM-1 inhibitors. Bioorg. Med. Chem. Lett., 2014, 24, 386-389.
[24]
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, 503-506.
[25]
Zhang, J.; Wang, S.; Wei, Q.; Guo, Q.; Bai, Y.; Yang, S.; Song, F.; Zhang, L.; Lei, X. Synthesis and biological evaluation of Aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance. Bioorg. Med. Chem., 2017, 25, 5133-5141.
[26]
Jones, G.; Willett, P.; Glen, R.C.; Leach, A.R.; Taylor, R. Development and validation of a genetic algorithm for flexible docking. J. Mol. Biol., 1997, 267, 727-748.
[27]
Eldridge, M.D.; Murray, C.W.; Auton, T.R.; Paolini, G.V.; Mee, R.P. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes. J. Comput. Aided Mol. Des., 1997, 11, 425-445.
[28]
Jain, A.N. Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J. Comput. Aided Mol. Des., 1996, 10, 427-440.
[29]
Kuntz, I.D.; Blaney, J.M.; Oatley, S.J.; Langridge, R.; Ferrin, T.E. A geometric approach to macromolecule-ligand interactions. J. Mol. Biol., 1982, 161, 269-288.
[30]
Zhang, F.; Li, C.; Qi, C. Highly diastereo- and enantioselective direct aldol reaction under solvent-free conditions. Tetrahedron Asymmetry, 2013, 24, 380-388.
[31]
Anderson, W.K.; Corey, P.F. Synthesis and antileukemic activity of 5-substituted 2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrroli-zine diesters. J. Med. Chem., 1977, 20, 812-818.
[32]
Sasikala, D.; Jeyakanthan, J.; Srinivasan, P. Structure-based virtual screening and biological evaluation of LuxT inhibitors for targeting quorum sensing through an in vitro biofilm formation. J. Mol. Struct., 2017, 1127, 322-336.
[33]
Haltiner, R.C.; Migneault, P.C.; Roberston, R.G. Incidence of thymidine-dependent enterococci detected on mueller-hinton agar with low thymidine content. Anti. Ag. Chem., 1980, 18, 365-368.
[34]
Adamski, C.J.; Cardenas, A.M.; Brown, N.G.; Horton, L.B.; Sankaran, B.; Prasad, B.V.; Gilbert, H.F.; Palzkill, T. Molecular basis for the catalytic specificity of the CTX-M extended-spectrum β-lactamases. Biochemistry, 2015, 54, 447-457.

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