In silico identification and experimental validation of hits active against KPC-2 β-lactamase

PLoS ONE

Volumn 13, Issue 11, 2018, Pages

  Klein, Raphael ^a   Linciano, Pasquale ^b   Celenza, Giuseppe ^c   Bellio, Pierangelo ^c   Papaioannou, Sofia ^b   Blazquez, Jesus ^d   Cendron, Laura ^e   Brenk, Ruth ^f   Tondi, Donatella ^b  

^a JOHANNES GUTENBERG UNIVERSITY   (Germany)

^b UNIVERSITY OF MODENA AND REGGIO EMILIA   (Italy)

^c UNIVERSITY OF L'AQUILA   (Italy)

^d CSIC   (Spain)

^e UNIVERSITY OF PADOVA   (Italy)

^f UNIVERSITY OF BERGEN   (Norway)

Author keywords

[No Author keywords available]

Indexed keywords

AVIBACTAM; BETA LACTAMASE; BETA LACTAMASE INHIBITOR; BETA LACTAMASE KPC 2; MEROPENEM; N [3 (1H TETRAZOL 5 YL)PHENYL] 3 FLUOROBENZAMIDE; N [3 (1H TETRAZOL 5 YL)PHENYL] 3 FLUOROBENZENESULFONAMIDE; N [3 (1H TETRAZOL 5 YL)PHENYL] 3 NITROBENZENESULFONAMIDE; N [3 (1H TETRAZOL 5 YL)PHENYL] 4 CHLOROBENZENESULFONAMIDE; N [3 (1H TETRAZOL 5 YL)PHENYL] 5 (DIMETHYLAMINO)NAPHTHALENE 1 SULFONAMIDE; N [3 (1H TETRAZOL 5 YL)PHENYL]QUINOLINE 8 SULFONAMIDE; N [4 [N [3 (1H TETRAZOL 5 YL)PHENYL]SULFAMOYL]PHENYL]ACETAMIDE; UNCLASSIFIED DRUG; VABORBACTAM; BACTERIAL PROTEIN; BETA-LACTAMASE KPC-2, KLEBSIELLA PNEUMONIAE;

ANTIBACTERIAL ACTIVITY; ANTIBIOTIC RESISTANCE; ARTICLE; BACTERIAL GENE; BINDING AFFINITY; BINDING SITE; BLA GENE; CONTROLLED STUDY; DRUG ANTAGONISM; DRUG POTENCY; DRUG SCREENING; DRUG SOLUBILITY; DRUG STABILITY; DRUG STRUCTURE; ENZYME BINDING; ENZYME CONFORMATION; ENZYME INHIBITION; ESCHERICHIA COLI; GENE EXPRESSION; HYDROGEN BOND; HYDROLYSIS; HYDROPHILICITY; IC50; IN VITRO STUDY; KLEBSIELLA PNEUMONIAE; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PROTEIN EXPRESSION; VALIDATION PROCESS; ANTAGONISTS AND INHIBITORS; CHEMISTRY; ENZYME ACTIVE SITE; ENZYMOLOGY;

BACTERIAL PROTEINS; BETA-LACTAMASE INHIBITORS; BETA-LACTAMASES; CATALYTIC DOMAIN; KLEBSIELLA PNEUMONIAE;

EID: 85057557098     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0203241     Document Type: Article

References (46)

1. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: Past, present, and future. Antimicrob Agents Chemother. 2011; 55: 4943–4960. https://doi.org/10.1128/AAC.00296-11 PMID: 21859938
2. Tondi D, Cross S, Venturelli A, Costi MP, Cruciani G, Spyrakis F. Decoding the Structural Basis For Carbapenem Hydrolysis By Class A beta-lactamases: Fishing For A Pharmacophore. Curr Drug Targets. Netherlands; 2016; 17: 983–1005. PMID: 26424401
3. Livermore DM, Woodford N. The beta-lactamase threat in Enterobacteriaceae, Pseudomonas and Aci-netobacter. Trends Microbiol. England; 2006; 14: 413–420. https://doi.org/10.1016/j.tim.2006.07.008PMID: 16876996
4. Farina D, Spyrakis F, Venturelli A, Cross S, Tondi D, Paola Costi M. The Inhibition of Extended Spectrum β-Lactamases: Hits and Leads. Current Medicinal Chemistry. 2014, pp. 1405–1434. PMID: 24180276
5. Frère J-M, Sauvage E, Kerff F. From “An Enzyme Able to Destroy Penicillin” to Carbapenemases: 70 Years of Beta-lactamase Misbehaviour. Current Drug Targets. 2016. pp. 974–982. PMID: 26424390
6. Naas T, Dortet L, Iorga B.I. Structural and Functional Aspects of Class A Carbapenemases. Current Drug Targets. 2016, pp. 1006–1028. https://doi.org/10.2174/1389450117666160310144501 PMID: 26960341
7. Papp-Wallace KM, Bethel CR, Distler AM, Kasuboski C, Taracila M, Bonomo RA. Inhibitor resistance in the KPC-2 beta-lactamase, a preeminent property of this class A beta-lactamase. Antimicrob Agents Chemother. United States; 2010; 54: 890–897. https://doi.org/10.1128/AAC.00693-09 PMID: 20008772
8. Brem J, Cain R, Cahill S, McDonough MA, Clifton IJ, Jiménez-Castellanos J-C, et al. Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates. 2016; 7: 12406. https://doi.org/10.1038/ncomms12406 PMID: 27499424
9. Santucci M, Spyrakis F, Cross S, Quotadamo A, Farina D, Tondi D, et al. Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases. Sci Rep. 2017; 7: 1–15. https://doi.org/10.1038/s41598-016-0028-x
10. Danishuddin M, Khan AU. Structure based virtual screening to discover putative drug candidates: Necessary considerations and successful case studies. Methods. 2015; 71: 135–145. https://doi.org/10.1016/j.ymeth.2014.10.019 PMID: 25448480
11. Khan A, Faheem M, Danishuddin M, Khan AU. Evaluation of Inhibitory Action of Novel Non β-Lactam Inhibitor against Klebsiella pneumoniae Carbapenemase (KPC-2). PLoS One. Public Library of Science; 2014; 9: e108246. https://doi.org/10.1371/journal.pone.0108246 PMID: 25265157
12. Krishnan NP, Nguyen NQ, Papp-Wallace KM, Bonomo RA, van den Akker F. Inhibition of Klebsiella β-Lactamases (SHV-1 and KPC-2) by Avibactam: A Structural Study. PLoS One. Public Library of Science; 2015; 10: e0136813. https://doi.org/10.1371/journal.pone.0136813 PMID: 26340563
13. Pemberton OA, Zhang X, Chen Y. Molecular Basis of Substrate Recognition and Product Release by the Klebsiella pneumoniae Carbapenemase (KPC-2). J Med Chem. United States; 2017; 60: 3525–3530. https://doi.org/10.1021/acs.jmedchem.7b00158 PMID: 28388065
14. Ito JI, Tabei Y, Shimizu K, Tsuda K, Tomii K. PoSSuM: A database of similar protein-ligand binding and putative pockets. Nucleic Acids Res. 2012; 40: 541–548. https://doi.org/10.1093/nar/gkr701
15. Ito JI, Ikeda K, Yamada K, Mizuguchi K, Tomii K. PoSSuM v.2.0: Data update and a new function for investigating ligand analogs and target proteins of small-molecule drugs. Nucleic Acids Res. 2015; 43: D392–D398. https://doi.org/10.1093/nar/gku1144 PMID: 25404129
16. Ke W, Bethel CR, Papp-Wallace KM, Pagadala SRR, Nottingham M, Fernandez D, et al. Crystal structures of KPC-2 beta-lactamase in complex with 3-nitrophenyl boronic acid and the penam sulfone PSR-3-226. Antimicrob Agents Chemother. United States; 2012; 56: 2713–2718. https://doi.org/10.1128/AAC.06099-11 PMID: 22330909
17. Nichols DA, Jaishankar P, Larson W, Smith E, Liu G, Beyrouthy R, et al. Structure-based design of potent and ligand-efficient inhibitors of CTX-M class A β-lactamase. J Med Chem. 2012; 55: 2163–2172. https://doi.org/10.1021/jm2014138 PMID: 22296601
18. Tomanicek SJ, Standaert RF, Weiss KL, Ostermann A, Schrader TE, Ng JD, et al. Neutron and X-ray Crystal Structures of a Perdeuterated Enzyme Inhibitor Complex Reveal the Catalytic Proton Network of the Toho-1 β-Lactamase for the Acylation Reaction. J Biol Chem. 9650 Rockville Pike, Bethesda, MD 20814, U.S.A.: American Society for Biochemistry and Molecular Biology; 2013; 288: 4715–4722. https://doi.org/10.1074/jbc.M112.436238 PMID: 23255594
19. Chen Y, Shoichet BK. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat Chem Biol. 2009; 5: 358–364. https://doi.org/10.1038/nchembio.155 PMID: 19305397
20. Fonseca F, Chudyk EI, van der Kamp MW, Correia A, Mulholland AJ, Spencer J. The Basis for Carbapenem Hydrolysis by Class A β-Lactamases: A Combined Investigation using Crystallography and Simulations. J Am Chem Soc. American Chemical Society; 2012; 134: 18275–18285. https://doi.org/10.1021/ja304460j PMID: 23030300
21. Ambler RP, Coulson AF, Frere JM, Ghuysen JM, Joris B, Forsman M, et al. A standard numbering scheme for the class A beta-lactamases. The Biochemical journal. England; 1991. pp. 269–270.
22. Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson J, et al. Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem. 2008; 3: 435–444. https://doi.org/10.1002/cmdc.200700139 PMID: 18064617
23. Hawkins PCD, Skillman AG, Warren GL, Ellingson BA, Stahl MT. Conformer Generation with OMEGA: Algorithm and Validation Using High Quality Structures from the Protein Databank and Cambridge Structural Database. J Chem Inf Model. American Chemical Society; 2010; 50: 572–584. https://doi.org/10.1021/ci100031x PMID: 20235588
24. Mpamhanga CP, Spinks D, Tulloch LB, Shanks EJ, Robinson DA, Collie IT, et al. One scaffold, three binding modes: Novel and selective pteridine reductase 1 inhibitors derived from fragment hits discovered by virtual screening. J Med Chem. 2009; 52: 4454–4465. https://doi.org/10.1021/jm900414xPMID: 19527033
25. Brenk R, Irwin JJ, Shoichet BK. Here Be Dragons: Docking and Screening in an Uncharted Region of Chemical Space. J Biomol Screen. 2005; 10: 667–674. https://doi.org/10.1177/1087057105281047PMID: 16170052
26. Mysinger MM, Shoichet BK. Rapid context-dependent ligand desolvation in molecular docking. J Chem Inf Model. 2010; 50: 1561–1573. https://doi.org/10.1021/ci100214a PMID: 20735049
27. Lorber DM, Shoichet BK. Flexible ligand docking using conformational ensembles. Protein Sci. 1998; 7: 938–950. https://doi.org/10.1002/pro.5560070411 PMID: 9568900
28. Wei BQ, Baase WA, Weaver LH, Matthews BW, Shoichet BK. A Model Binding Site for Testing Scoring Functions in Molecular Docking. J Mol Biol. 2002; 322: 339–355. https://doi.org/10.1016/S0022-2836 (02)00777-5 PMID: 12217695
29. Kuntz ID, Chen K, Sharp KA, Kollman PA. The maximal affinity of ligands. Proc Natl Acad Sci. 1999; 96: 9997–10002. PMID: 10468550
30. Hopkins AL, Groom CR, Alex A. Ligand efficiency: a useful metric for lead selection. Drug Discov Today. 2004; 9: 430–431. https://doi.org/10.1016/S1359-6446(04)03069-7 PMID: 15109945
31. Celenza G, Vicario M, Bellio P, Linciano P, Perilli M, Oliver A, et al. Phenylboronic Acid Derivatives as Validated Leads Active in Clinical Strains Overexpressing KPC-2: A Step against Bacterial Resistance. ChemMedChem. 2018; https://doi.org/10.1002/cmdc.201700788 PMID: 29356380
32. Crompton R, Williams H, Ansell D, Campbell L, Holden K, Cruickshank S, et al. Oestrogen promotes healing in a bacterial LPS model of delayed cutaneous wound repair. Lab Invest. United States; 2016; 96: 439–449. https://doi.org/10.1038/labinvest.2015.160 PMID: 26855364
33. Feng BY, Shoichet BK. A detergent-based assay for the detection of promiscuous inhibitors. Nat Pro-toc. England; 2006; 1: 550–553. https://doi.org/10.1038/nprot.2006.77 PMID: 17191086
34. Quotadamo A, Linciano P, Davoli P, Tondi D, Costi MP, Venturelli A. An Improved Synthesis of CENTA, a Chromogenic Substrate for β-Lactamases. Synlett. 2016; 27: 2447–2450. https://doi.org/10.1055/s-0035-1562454
35. Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. England; 1973; 22: 3099–3108. PMID: 4202581
36. Strynadka NC, Adachi H, Jensen SE, Johns K, Sielecki A, Betzel C, et al. Molecular structure of the acyl-enzyme intermediate in beta-lactam hydrolysis at 1.7 A resolution. Nature. England; 1992; 359: 700–705. https://doi.org/10.1038/359700a0 PMID: 1436034
37. Tondi D, Venturelli A, Bonnet R, Pozzi C, Shoichet BK, Costi MP. Targeting class A and C serine beta-lactamases with a broad-spectrum boronic acid derivative. J Med Chem. United States; 2014; 57: 5449–5458. https://doi.org/10.1021/jm5006572 PMID: 24882105
38. Genovese F, Lazzari S, Venturi E, Costantino L, Blazquez J, Ibacache-Quiroga C, et al. Design, synthesis and biological evaluation of non-covalent AmpC β-lactamases inhibitors. Med Chem Res. 2017; 26: 975–986. https://doi.org/10.1007/s00044-017-1809-x
39. Congreve M, Carr R, Murray C, Jhoti H. A “rule of three” for fragment-based lead discovery? Drug Discov Today. England; 2003; 8: 876–877.
40. Popa-Burke I, Russell J. Compound precipitation in high-concentration DMSO solutions. J Biomol Screen. 2014; 19: 1302–1308. https://doi.org/10.1177/1087057114541146 PMID: 24980595
41. Bembenek SD, Tounge BA, Reynolds CH. Ligand efficiency and fragment-based drug discovery. Drug Discov Today. 2009; 14: 278–283. https://doi.org/10.1016/j.drudis.2008.11.007 PMID: 19073276
42. Popa-Burke IG, Issakova O, Arroway JD, Bernasconi P, Chen M, Coudurier L, et al. Streamlined system for purifying and quantifying a diverse library of compounds and the effect of compound concentration measurements on the accurate interpretation of biological assay results. Anal Chem. 2004; 76: 7278–7287. https://doi.org/10.1021/ac0491859 PMID: 15595870
43. Seidler J, McGovern SL, Doman TN, Shoichet BK. Identification and Prediction of Promiscuous Aggregating Inhibitors among Known Drugs. J Med Chem. American Chemical Society; 2003; 46: 4477–4486. https://doi.org/10.1021/jm030191r PMID: 14521410
44. Vijayadas KN, Davis HC, Kotmale AS, Gawade RL, Puranik VG, Rajamohanan PR, et al. An unusual conformational similarity of two peptide folds featuring sulfonamide and carboxamide on the backbone. Chem Commun. The Royal Society of Chemistry; 2012; 48: 9747–9749. https://doi.org/10.1039/ C2CC34533A PMID: 22914747
45. Babaoglu K, Shoichet BK. Deconstructing fragment-based inhibitor discovery. Nature chemical biology. United States; 2006. pp. 720–723. https://doi.org/10.1038/nchembio831 PMID: 17072304
46. Verdonk ML, Giangreco I, Hall RJ, Korb O, Mortenson PN, Murray CW. Docking Performance of Fragments and Druglike Compounds. J Med Chem. American Chemical Society; 2011; 54: 5422–5431. https://doi.org/10.1021/jm200558u PMID: 21692478