Metallo-β-Lactamases: A Major Threat to Human Health


Antibiotic resistance is one of the most significant challenges facing global healthcare. Since the 1940s, antibiotics have been used to fight infections, initially with penicillin and subsequently with various derivatives including cephalosporins, carbapenams and monobactams. A common characteristic of these antibiotics is the four-memberedβ-lactam ring. Alarmingly, in recent years an increasing number of bacteria have become resistant to these antibiotics. A major strategy employed by these pathogens is to use Zn(II)-dependent enzymes, the metallo-β-lactamases (MBLs), which hydrolyse theβ-lactam ring. Clinically useful MBL inhibitors are not yet available. Consequently, MBLs remain a major threat to human health. In this review biochemical properties of MBLs are discussed, focusing in particular on the interactions between the enzymes and the functionally essential metal ions. The precise role(s) of these metal ions is still debated and may differ between different MBLs. However, since they are required for catalysis, their binding site may present an alternative target for inhibitor design.

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Phelan, E. , Miraula, M. , Selleck, C. , Ollis, D. , Schenk, G. and Mitić, N. (2014) Metallo-β-Lactamases: A Major Threat to Human Health. American Journal of Molecular Biology, 4, 89-104. doi: 10.4236/ajmb.2014.43011.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Davies, J. (1994) Inactivation of Antibiotics and the Dissemination of Resistance Genes. Science, 264, 375-382.
[2] Bebrone, C. (2007) Metallo-β-Lactamases (Classification, Activity, Genetic Organization, Structure, Zinc Coordination) and Their Superfamily.Biochemical Pharmacology, 74, 1686-1701.
[3] Galleni, M., Lamotte-Brasseur, J., Rossolini, G.M., Spencer, J., Dideberg, O. and Frère, J.M. (2001) Standard Numbering Scheme for Class B β-Lactamases.Antimicrobial agents and chemotherapy, 45, 660-663.
[4] Bebrone, C., Lassaux, P., Vercheval, L., Sohier, J.S., Jehaes, A., Sauvage, E. and Galleni, M. (2010) Current Challenges in Antimicrobial Chemotherapy Focus on β-Lactamase Inhibition. Drugs, 70, 651-679.
[5] Pérez-Llarena, F.J. and Bou, G. (2009) β-Lactamase Inhibitors: The Story so Far. Current Medicinal Chemistry, 16, 3740-3765.
[6] Maltezou, H.C. (2009) Metallo-β-Lactamases in Gram-Negative Bacteria: Introducing the Era of Pan-Resistance? International Journal of Antimicrobial Agents, 33, 405.e1-405.e7.
[7] Perez, F., Hujer, A.M., Hujer, K.M., Decker, B.K., Rather, P.N. and Bonomo, R.A. (2007) Global Challenge of Multidrug-Resistant. Acinetobacter baumannii Antimicrobial Agents and Chemotherapy, 51, 3471-3484.
[8] Pollini. S., Maradei, S., Pecile, P., Olivo, G., Luzzaro, F., Docquier, J.D. and Rossolini, G.M. (2013) FIM-1, a New Acquired Metallo—Lactamase from a Pseudomonas aeruginosa Clinical Isolate from Italy. Antimicrobial Agents and Chemotherapy, 57, 410-416.
[9] Nordmann, P. and Poirel, L. (2012) Strategies for Identification of Carbapenemase-Producing Enterobacteriaceae. Journal of Antimicrobial Chemotherapy, 68, 487-489.
[10] Livermore, D.M. and Woodford, N. (2006) The b-Lactamase Threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends in Microbiology, 14, 413-420.
[11] Lee, K., Yum, J. H., Yong, D., Lee, H.M., Kim, H.D., Docquier, J.-D., Rossolini, G.M. and Chong, Y. (2005) Novel Acquired Metallo-β-Lactamase Gene, blaSIM-1, in a Class 1 Integron from Acinetobacter baumannii Clinical Isolates from Korea. Antimicrobial Agents and Chemotherapy, 49, 4485-4491.
[12] Heinz, U. and Adolph, H.W. (2004) Metallo-β-Lactamases: Two Binding Sites for One Catalytic Metal Ion? Cellular and Molecular Life Sciences, 61, 2827-2839.
[13] Page, M. I. and Badarau, A. (2008) Loss of Enzyme Activity during Turnover of the Bacillus cereus β-Lactamase Catalysed Hydrolysis of b-Lactams Due to Loss of Zinc Ion. Journal of Bioilogical Inorganic Chemistry, 13, 919-928.
[14] Crowder, M.W., Spencer, J. and Vila, A.J. (2006) Metallo-β-Lactamases: Novel Weaponry for Antibiotic Resistance in Bacteria. Accounts of Chemical Research, 39, 721-728.
[15] Hou, C.F., Phelan E.K., Miraula, M., Ollis, D.L., Schenk, G. and Mitic, N. (2014) Unusual Metallo-β-Lactamases May Constitute a New Subgroup in This Family of Enzymes. American Journal of Molecular Biology, 4, 11-15.
[16] Guo, Y., Wang, J., Niu, G.J., Shui, W.Q., Sun, Y.N., Zhou, H.G., Zhang, Y.Z., Yang, C., Lou, Z.Y. and Rao, Z.H. (2011) A Structural View of the Antibiotic Degradation Enzyme NDM-1 from a Superbug. Protein & Cell, 2, 384-395.
[17] Llarrull, L.I., Tioni, M.F. and Vila, A.J. (2008) Metal Content and Localization during Turnover in B. cereus Metallo-β-Lactamase. Journal of the American Chemical Society, 130, 15842-15851.
[18] Rasia, R.M. and Vila, A.J. (2002) Exploring the Role and the Binding Affinity of a Second Zinc Equivalent in B. cereus Metallo-β-Lactamase. Biochemistry, 41, 1853-1860.
[19] Valladares, M.H., Kiefer, M., Heinz, U., Soto, R.P., Meyer-Klaucke, W., Nolting, H.F., Zeppezauer, M., Galleni, M., Frere, J.M., Rossolini, G.M., Amicosante, G. and Adolph, H.W. (2000) Kinetic and Spectroscopic Characterization of Native and Metal-Substituted β-Lactamase from Aeromonas hydrophila AE036. FEBS Letters, 467, 221-225.
[20] Massida, O., Rossolini, G.M. and Satta, G. (1991) The Aeromonas hydrophila cphA Gene: Molecular Heterogeneity among Class B Metallo-β-Lactamases. Journal of Bacteriology, 173, 4611-4617.
[21] Segatore, B., Massidda, O., Satta, G., Setacci, D. and Amicosante, G. (1993) High Specificity of cphA-Encoded Metallo-β-Lactamase from Aeromonas hydrophila AE036 for Carbapenems and Its Contribution to β-Lactam Resistance. Antimicrobial Agents and Chemotherapy, 37, 1324-1328.
[22] Bebrone, C., Anne, C., De Vriendt, K., Devreese, B., Rossolini, G.M., Van Beeumen, J., Frere, J.M. and Galleni, M. (2005) Dramatic Broadening of the Substrate Profile of the Aeromonas hydrophila CphA Metallo-β-Lactamase by Site-Directed Mutagenesis. The Journal of Biological Chemistry, 280, 28195-28202.
[23] Leiros, H.L.S., Borra, P.S., Brandsdal, B.O., Edvardsen, K.S.W., Spencer, J., Walsh, T.R. and Samuelson, O. (2012) Crystal Structure of the Mobile Metallo-β-Lactamase AIM-1 from Pseudomonas aeruginosa: Insights into Antibiotic Binding and the Role of Gln157. Antimicrobial Agents and Chemotherapy, 56, 4341-4353.
[24] Costello, A., Periyannan, G., Yang, K.W., Crowder, M.W. and Tierney, D.L. (2006) Site-Selective Binding of Zn(II) to Metallo-β-Lactamase L1 from Stenotrophomonas maltophilia. Journal of Biological Inorganic Chemistry, 11, 351-358.
[25] Vella, P., Miraula, M., Phelan, E.K., Leung, E.W., Ely, F., Ollis, D.L., McGeary, R.P., Schenk, G. and Mitic, N. (2013) Identification and Characterization of an Unusual Metallo-β-Lactamase from Serratia proteamaculans. Journal of Biological Inorganic Chemistry, 18, 855-863.
[26] Jackson, C.J., Hadler, K.S., Carr, P.D., Oakley, A.J., Yip, S., Schenk, G. and Ollis, D.L. (2008) Malonate-Bound Structure of the Glycerophosphodiesterase from Enterobacter aerogenes (GpdQ) and Characterization of the Native Fe2+ Metal-Ion Preference. Acta Crystallographica Section F: Structural Biology and Crystallization Communications, 64, 681-685.
[27] Hadler, K.S., Tanifum, E.A., Yip, S.H.C., Mitìc, N., Guddat, L.W., Jackson, C.J., Gahan, L.R., Nguyen, K., Carr, P.D., Ollis, D.L., Hengge, A.C., Larrabee, J.A. and Schenk, G. (2008) Substrate-Promoted Formation of a Catalytically Competent Binuclear Center and Regulation of Reactivity in a Glycerophosphodiesterase from Enterobacter aerogenes. Journal of the American Chemical Society, 130, 14129-14138.
[28] Hadler, K.S., Mitic, N., Ely, F., Hanson, G.R., Gahan, L.R., Larrabee, J.A., Ollis, D.L. and Schenk, G. (2009) Structural Flexibility Enhances the Reactivity of the Bioremediator Glycerophosphodiesterase by Fine-Tuning Its Mechanism of Hydrolysis. Journal of the American Chemical Society, 131, 11900-11908.
[29] Hadler, K.S., Mitic, N., Yip, S.H., Gahan, L.R., Ollis, D.L., Schenk, G. and Larrabee, J.A. (2010) Electronic Structure Analysis of the Dinuclear Metal Center in the Bioremediator Glycerophosphodiesterase (GpdQ) from Enterobacter aerogenes. Inorganic Chemistry, 49, 2727-2734.
[30] Hadler, K.S., Gahan, L.R., Ollis, D.L. and Schenk, G. (2010) The Bioremediator Glycerophosphodiesterase Employs a Non-Processive Mechanism for Hydrolysis. Journal of Inorganic Biochemistry, 104, 211-213.
[31] Yip, S.H.C., Foo, J.L., Schenk, G., Gahan, L.R., Carr, P.D. and Ollis, D.L. (2011) Directed Evolution Combined with Rational Design Increases Activity of GpdQ toward a Non-Physiological Substrate and Alters the Oligomeric Structure of the Enzyme. Protein Engineering Design and Selection, 24, 861-872.
[32] Schenk, G., Mitic, N., Gahan, L.R., Ollis, D.L., McGeary, R.P. and Guddat, L.W. (2012) Binuclear Metallohydrolases: Complex Mechanistic Strategies for a Simple Chemical Reaction. Accounts of Chemical Research, 45, 1593-1603.
[33] Daumann, L.J., McCarthy, B.Y., Hadler, K.S., Murray, T.P., Gahan, L.R., Larrabee, J.A., Ollis, D.L. and Schenk, G. (2013) Promiscuity Comes at a Price: Catalytic Versatility vs Efficiency in Different Metal Ion Derivatives of the Potential Bioremediator GpdQ. Biochimica et Biophysica Acta, 1834, 425-432.
[34] Badarau, A. and Page, M.I. (2006) The Variation of Catalytic Efficiency of Bacillus cereus Metallo-β-Lactamase with Different Active Site Metal Ions. Biochemistry, 45, 10654-10666.
[35] Carfi, A., Pares, S., Duee, E., Galleni, M., Duez, C., Frere, J.M. and Dideberg, O. (1995) Spectroscopic Characterization of a Binuclear Metal Site in Bacillus cereus β-Lactamase II. EMBO Journal, 14, 4914-4921.
[36] Concha, N.O., Janson, C.A., Rowling, P., Pearson, S., Cheever, C.A., Clarke, B.P., Lewis, C., Galleni, M., Frere, J.M., Payne, D.J., Bateson, J.H. and Abdel-Meguid, S.S. (2000) Crystal Structure of the IMP-1 Metallo β-Lactamase from Pseudomonas aeruginosa and Its Complex with a Mercaptocarboxylate Inhibitor: Binding Determinants of a Potent, Broad-Spectrum Inhibitor. Biochemistry, 39, 4288-4298.
[37] Bellais, S., Girlich, D., Karim, A. and Nordmann, P. (2002) EBR-1, a Novel Ambler Subclass B1 β-Lactamase from Empedobacter brevis. Antimicrobial Agents and Chemotherapy, 46, 3223-3227.
[38] Yamaguchi, Y., Takashio, N., Wachino, J., Yamagata, Y., Arakawa, Y., Matsuda, K. and Kurosaki, H. (2010) Structure of Metallo-β-Lactamase IND-7 from a Chryseobacterium indologenes Clinical Isolate at 1.65—A Resolution. Journal of Biochemistry, 147, 905-915.
[39] Borra, P.S., Samuelsen, O., Spencer, J., Walsh, T.R., Lorentzen, M.S. and Leiros, H.K. (2013) Crystal Structures of Pseudomonas aeruginosa GIM-1: Active-Site Plasticity in Metallo-β-Lactamases. Antimicrobial Agents and Chemotherapy, 57, 848-854.
[40] Poirel, L., Héritier, C. and Nordmann, P. (2005) Genetic and Biochemical Characterization of the Chromosome-Encoded Class B β-Lactamases from Shewanella livingstonensis (SLB-1) and Shewanella frigidimarina (SFB-1). Journal of Antimicrobial Chemotherapy, 55, 680-685.
[41] Laraki, N., Franceschini, N., Rossolini, G.M., Santucci, P., Meunier, C., de Pauw, E., Amicosante, G., Frere, J.M. and Galleni, M. (1999) Biochemical Characterization of the Pseudomonas aeruginosa 101/1477 Metallo-β-Lactamase IMP-1 Produced by Escherichia coli. Antimicrobial Agents and Chemotherapy, 43, 902-906.
[42] Iyobe, S., Kusadokoro, H., Ozaki, J., Matsumura, N., Minami, S., Haruta, S., Sawai, T. and O’Hara, K. (2000) Amino Acid Substitutions in a Variant of IMP-1 Metallo-β-Lactamase. Antimicrobial Agents and Chemotherapy, 44, 2023-2027.
[43] Riccio, M.L., Franceschini, N., Boschi, L., Caravelli, B., Cornaglia, G., Fontana, R., Amicosante, G. and Rossolini, G.M. (2000) Characterization of the Metallo-β-Lactamase Determinant of Acinetobacter baumannii AC-54/97 Reveals the Existence of bla(IMP) Allelic Variants Carried by Gene Cassettes of Different Phylogeny. Antimicrobial Agents and Chemotherapy, 44, 1229-1235.
[44] Oelschlaeger, P. and Mayo, S. (2005) Hydroxyl Groups in the ββ Sandwich of Metallo-β-Lactamases Favor Enzyme Activity: A Computational Protein Design Study. Journal of Molecular Biochemistry, 350, 395-401.
[45] Yamaguchi, Y., Ding, S., Murakami, E., Imamura, K., Fuchigami, S., Hashiguchi, R., Yutani, K., Mori, H., Suzuki, S., Arakawa, Y. and Kurosaki, H. (2011) A Demetallation Method for IMP-1 Metallo-β-Lactamase with Restored Enzymatic Activity upon Addition of Metal Ion(s). ChemBiochem, 12, 1979-1983.
[46] Griffin, D.H., Richmond, T.K., Sanchez, C., Moller, A.J., Breece, R.M., Tierney, D.L., Bennett, B. and Crowder, M.W. (2011) Structural and Kinetic Studies on Metallo-β-Lactamase IMP-1. Biochemistry, 50, 9125-9134.
[47] Vella, P., Hussein, W.M., Leung, E.W., Clayton, D., Ollis, D.L., Mitic, N., Schenk, G. and McGeary, R.P. (2011) The Identification of New Metallo-β-Lactamase Inhibitor Leads from Fragment-Based Screening. Bioorganic & Medicinal Chemistry Letters, 21, 3282-3285.
[48] Horton, L.B., Shanker, S., Mikulski, R., Brown, N.G., Phillips, K.J., Lykissa, E., Venkataram Prasad, B.V. and Palzkill, T. (2012) Mutagenesis of Zinc Ligand Residue Cys221 Reveals Plasticity in the IMP-1 Metallo-β-Lactamase Active Site. Antimicrobial Agents and Chemotherapy, 56, 5667-5677.
[49] Lauretti, L., Riccio, M.L., Mazzariol, A., Cornaglia, G., Amicosante, G., Fontana, R. and Rossolini, G.M. (1999) Cloning and Characterization of blaVIM, a New Integron-Borne Metallo-β-Lactamase Gene from a Pseudomonas aeruginosa Clinical Isolate. Antimicrobial Agents and Chemotherapy, 43, 1584-1590.
[50] Cornaglia, G., Mazzariol, A., Lauretti, L., Rossolini, G.M. and Fontana, R. (2000) Hospital Outbreak of Carbapenem-Resistant Pseudomonas aeruginosa Producing VIM-1, a Novel Transferable Metallo-β-Lactamase. Clinical Infectious Diseases, 31, 1119-1125.
[51] Tsakris, A., Pournaras, S., Woodford, N., Palepou, M.F., Babini, G.S., Douboyas, J. and Livermore, D.M. (2000) Out-break of Infections Caused by Pseudomonas aeruginosa Producing VIM-1 Carbapenemase in Greece. Journal of Clinical Microbiology, 38, 1290-1292.
[52] Giakkoupi, P., Xanthaki, A., Kanelopoulou, M., Vlahaki, A., Miriagou, V., Kontou, S., Papafraggas, E., Malamou-Lada, H., Tzouvelekis, L., Legakis, N. and Vatopoulos, A.C. (2003) VIM-1 Metallo-β-Lactamase-Producing Klebsiella pneumoniae Strains in Greek Hospitals. Journal of Clinical Microbiology, 41, 3893-3896.
[53] Pournaras, S., Maniati, M., Petinaki, E., Tzouvelekis, L., Tsakris, A., Legakis, N. and Maniatis, A. (2003) Hospital Outbreak of Multiple Clones of Pseudomonas aeruginosa Carrying the Unrelated Metallo-β-Lactamase Gene Variants blaVIM-2 and blaVIM-4. Journal of Antimicrobial Chemotherapy, 51, 1409-1414.
[54] Miriagou, V., Tzelepi, E., Gianneli, D. and Tzouvelekis, L.S. (2003) Escherichia coli with a Self-Transferable, Multiresistant Plasmid Coding for Metallo-β-Lactamase VIM-1. Antimicrobial Agents and Chemotherapy, 47, 395-397.
[55] Giske, C.G., Rylander, M. and Kronvall, G. (2003) VIM-4 in a Carbapenem-Resistant Strain of Pseudomonas aeruginosa Isolated in Sweden. Antimicrobial Agents and Chemotherapy, 47, 3034-3035.
[56] Luzzaro, F., Docquier, J.D., Colinon, C., Endimiani, A., Lombardi, G., Amicosante, G., Rossolini, G.M. and Toniolo, A. (2004) Emergence in Klebsiella pneumoniae and Enterobacter cloacae Clinical Isolates of the VIM-4 Metallo-β-Lactamase Encoded by a Conjugative Plasmid. Antimicrobial Agents and Chemotherapy, 48, 648-650.
[57] Ktari, S., Arlet, G., Mnif, B., Gautier, V., Mahjoubi, F., Jmeaa, M.B., Bouaziz, M. and Hammami, A. (2006) Emergence of Multidrug-Resistant Klebsiella pneumoniae Isolates Producing VIM-4 Metallo-β-Lactamase, CTX-M-15 Extended-Spectrum β-Lactamase, and CMY-4 AmpC β-Lactamase in a Tunisian University Hospital. Antimicrobial Agents and Chemotherapy, 50, 4198-4201.
[58] Garcia-Saez, I., Docquier, J.D., Rossolini, G.M. and Dideberg, O. (2008) The Three-Dimensional Structure of VIM-2, a Zn-β-Lactamase from Pseudomonas aeruginosa in Its Reduced and Oxidised Form. Journal of Molecular Biology, 375, 604-611.
[59] de Seny, D., Heinz, U., Wommer, S., Kiefer, M., Meyer-Klaucke, W., Galleni, M., Frere, J.M., Bauer, R. and Adolph, H.W. (2001) Metal Ion Binding and Coordination Geometry for Wild Type and Mutants of Metallo-β-Lactamase from Bacillus cereus 569/H/9 (BcII): A Combined Thermodynamic, Kinetic, and Spectroscopic Approach. Journal of Biological Chemistry, 276, 45065-45078.
[60] Abriata, L.A., González, L.J., Llarrull, L.I., Tomatis, P.E., Myers, W.K., Costello, A.L., Tierney, D.L. and Vila, A.J. (2008) Engineered Mononuclear Variants in Bacillus cereus Metallo-β-Lactamase BcII Are Inactive. Biochemistry, 47, 8590-8599.
[61] Yong, D., Toleman, M.A., Giske, C.G., Cho, H.S., Sundman, K., Lee, K. and Walsh, T.R. (2009) Characterization of a New Metallo-β-Lactamase Gene, blaNDM-1, and a Novel Erythromycin Esterase Gene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India. Antimicrobial Agents and Chemotherapy, 53, 5046-5054.
[62] Poirel, L., Hombrouck-Alet, C., Freneaux, C., Bernabeu, S. and Nordmann, P. (2010) Global Spread of New Delhi Metallo-β-Lactamase 1. The Lancet Infectious Diseases, 10, 832.
[63] Rolain, J.M., Parola, P. and Cornaglia, G. (2010) New Delhi Metallo-β-Lactamase (NDM-1): Towards a New Pandemia? Clinical Microbiology and Infection, 16, 1699-1701.
[64] Zhang, H.M. and Hao, Q. (2011) Crystal Structure of NDM-1 Reveals a Common β-Lactam Hydrolysis Mechanism. The FASEB Journal, 25, 2574-2582.
[65] Walsh, T.R., Weeks, J., Livermore, D.M. and Toleman, M.A. (2011) Dissemination of NDM-1 Positive Bacteria in the New Delhi Environment and Its Implications for Human Health: An Environmental Point Prevalence Study. The Lancet Infectious Diseases, 11, 355-362.
[66] Li, N., Xu, Y., Xia, Q., Bai, C., Wang, T., Wang, L., He, D., Xie, N., Li, L., Wang, J., et al. (2014) Simplified Captopril Analogues as NDM-1 Inhibitors. Bioinorganic and Medicinal Chemistry Letters, 24, 386-389.
[67] Crawford, P.A., Sharma, N., Chandrasekar, S., Sigdel, T., Walsh, T.R., Spencer, J. and Crowder, M.W. (2004) Over-Expression, Purification, and Characterization of Metallo-β-Lactamase ImiS from Aeromonas veronii bv. sobria. Protein Expression and Purification, 36, 272-279.
[68] Garau, G., Bebrone, C., Anne, C., Galleni, M., Frere, J.M. and Dideberg, O. (2005) A Metallo-β-Lactamase Enzyme in Action: Crystal Structures of the Monozinc Carbapenemase CphA and Its Complex with Biapenem. Journal of Molecular Biology, 345, 785-795.
[69] Xu, D.G., Zhou, Y.Z., Xie, D.Q. and Guo, H. (2005) Antibiotic Binding to Monozinc CphA β-Lactamase from Aeromonas hydropila: Quantum Mechanical/Molecular Mechanical and Density Functional Theory Studies. Journal of Medicinal Chemistry, 48, 6679-6689.
[70] Simona, F., Magistrato, A., Dal Peraro, M., Cavalli, A., Vila, A.J. and Carloni, P. (2009) Common Mechanistic Features among Metallo-β-Lactamases: A Computational Study of Aeromonas hydrophila CphA Enzyme. Journal of Biological Chemistry, 284, 28164-28171.
[71] Bebrone, C., Delbrück, H., Kupper, M.B., Schlömer, P., Willmann, C., Frère, J.M., Fischer, R., Galleni, M. and Hoffmann, K.M. (2009) The Structure of the Dizinc Subclass B2 Metallo-β-Lactamase CphA Reveals that the Second Inhibitory Zinc Ion Binds in the Histidine Site. Antimicrobial Agents and Chemotherapy, 53, 4464-4471.
[72] Fonseca, F., Bromley, E.H.C., Saavedra, M.J., Correia, A. and Spencer, J. (2011) Crystal Structure of Serratia fonticola Sfh-I: Activation of the Nucleophile in Mono-Zinc Metallo-β-Lactamases. Journal of Molecular Biology, 411, 951-959.
[73] Ullah, J.H., Walsh, T.R., Taylor, I.A., Emery, D.C., Verma, C.S., Gamblin, S.J. and Spencer, J. (1998) The Crystal Structure of the L1 Metallo-β-Lactamase from Stenotrophomonas maltophilia at 1.7 A Resolution. Journal of Molecular Biology, 284, 125-136.
[74] Hu, Z., Periyannan, G., Bennett, B. and Crowder, M.W. (2008) Role of the Zn1 and Zn2 Sites in Metallo-β-Lactamase L1. Journal of the American Chemical Society, 130, 14207-14216.
[75] Hu, Z., Periyannan, G.R. and Crowder, M.W. (2008) Folding Strategy to Prepare Co(II)-Substituted Metallo-β-Lactamase L1. Analytical Biochemistry, 378, 177-183.
[76] Garcia-Saez, I., Mercuri, P.S., Papamicael, C., Kahn, R., Frere, J.M., Galleni, M., Rossolini, G.M. and Dideberg, O. (2003) Three-Dimensional Structure of FEZ-1, a Monomeric Subclass B3 Metallo-β-Lactamase from Fluoribacter gormanii, in Native Form and in Complex with D-Captopril. Journal of Molecular Biology, 325, 651-660.
[77] Docquier, J.D., Benvenuti, M., Calderone, V., Stoczko, M., Menciassi, N., Rossolini, G.M. and Mangani, S. (2010) High-Resolution Crystal Structure of the Subclass B3 Metallo-β-Lactamase BJP-1: Rational Basis for Substrate Specificity and Interaction with Sulfonamides. Antimicrobial Agents and Chemotherapy, 54, 4343-4351.
[78] Miraula, M., Brunton, C.S., Schenk, G. and Mitic, N. (2013) Identification and Preliminary Characterization of Novel B3-Type Metallo-β-Lactamases. American Journal of Molecular Biology, 3, 198-203.
[79] Wachino, J.I., Yoshida, H., Yamane, K., Suzuki, S., Matsui, M., Yamagishi, T., Tsutsui, A., Konda, T., Shibayama, K. and Arakawa, Y. (2011) SMB-1, a Novel Subclass B3 Metallo-β-Lactamase, Associated with ISCR1 and a Class 1 Integron, from a Carbapenem-Resistant Serratia marcescens Clinical Isolate. Antimicrobial Agents and Chemotherapy, 55, 5143-5149.
[80] Stoczko, M., Frère, J.M., Rossolini, G.M. and Docquier, J.D. (2008) Functional Diversity among Metallo-β-Lactamases: Characterization of the CAR-1 Enzyme of Erwinia carotovora. Antimicrobial Agents and Chemotherapy, 52, 2473-2479.
[81] Docquier, J.D., Lopizzo, T., Liberatori, S., Prenna, M., Thaller, M.C., Frere, J.M. and Rossolini, G.M. (2004) Biochemical Characterization of the THIN-B Metallo-β-Lactamase of Janthinobacterium lividum. Antimicrobial Agents and Chemotherapy, 48, 4778-4783.
[82] Concha, N.O., Rasmussen, B.A., Bush, K. and Herzberg, O. (1996) Crystal Structure of the Wide-Spectrum Binuclear Zinc β-Lactamase from Bacteroides fragilis. Structure, 4, 823-836.
[83] Wang, Z., Fast, W., Valentine, A.M. and Benkovic, S.J. (1999) Metallo-β-Lactamase: Structure and Mechanism. Current Opinion in Chemical Biology, 3, 614-622.
[84] Paul-Soto, R., Bauer, R., Frere, J.M., Galleni, M., Meyer-Klaucke, W., Nolting, H., Rossolini, G.M., de Seny, D., Valladares, M., Zeppezauer, M. and Adolf, H.W. (1999) Mono- and Binuclear Zn2+-β-Lactamase. Role of the Conserved Cysteine in the Catalytic Mechanism. Journal of Biological Chemistry, 274, 13242-13249.
[85] Nauton, L., Khan, R., Garau, G., Hernandez, J.F. and Dideberg, O. (2008) Structural Insights into the Design of Inhibitors for the L1 Metallo-β-Lactamase from Stenotrophomonas maltophilia. Journal of Molecular Biology, 375, 257-269.
[86] Heinz, U., Bauer, R., Wommer, S., Meyer-Klaucke, W., Papamichaels, C., Bateson, J. and Adolph, H.W. (2003) Coordination Geometries of Metal Ions in D- or l-Captopril-Inhibited Metallo-β-Lactamases. Journal of Biological Chemistry, 278, 20659-20666.
[87] Garcia-Saez, I., Hopkins, J., Papamicael, C., Franceschini, N., Amicosante, G., Rossolini, G.M., Galleni, M., Frere, J.M. and Dideberg, O. (2003) The 1.5-A Structure of Chryseobacterium meningosepticum Zinc β-Lactamase in Complex with the Inhibitor, D-Captopril. Journal of Biological Chemistry, 278, 23868-23873.
[88] Wachino, J., Yamaguchi, Y., Mori, S., Kurosaki, H., Arakawa, Y. and Shibayama, K. (2013) Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate. Antimicrobial Agents and Chemotherapy, 57, 101-109.
[89] Mohamed, M.S., Hussein, W.M., McGeary, R.P., Vella, P., Schenk, G. and Abd El-hameed, R.H. (2011) Synthesis and Kinetic Testing of New Inhibitors for a Metallo-β-Lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. European Journal of Medicinal Chemistry, 46, 6075-6082.
[90] Faridoon, F.F., Hussein, W.M., Vella, P., Islam, N.U., Ollis, D.L., Schenk, G. and McGeary, R.P. (2012) 3-Mercapto-1,2,4-Triazoles and N-Acylated Thiosemicarbazides as Metallo-β-Lactamase Inhibitors. Bioorganic and Medicinal Chemistry Letters, 22, 380-386.
[91] Hussein, W.M., Fatahala, S.S., Mohamed, Z.M., McGeary, R.P., Schenk, G., Ollis, D.L. and Mohamed, M.S. (2012) Synthesis and Kinetic Testing of Tetrahydropyrimidine-2-Thione and Pyrrole Derivatives as Inhibitors of the Metallo-β-Lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa. Chemical Biology and Drug Design, 80, 500-515.
[92] McGeary, R.P., Schenk, G. and Guddat, L.W. (2014) The Applications of Binuclear Metallohydrolases in Medicine: Recent Advances in the Design and Development of Novel Drug Leads for Purple Acid Phosphatases, Metallo-β-Lactamases and Arginases. European Journal of Medicinal Chemistry, 76, 132-144.
[93] Murphy, T.A., Catto, L.E., Halford, S.E., Hadfield, A.T., Minor, W., Walsh, T.R. and Spencer, J. (2006) Crystal Structure of Pseudomonas aeruginosa SPM-1 Provides Insights into Variable Zinc Affinity of Metallo-β-Lactamases. Journal of Molecular Biology, 357, 890-903.
[94] Jacquin, O., Balbeur, D., Damblon, C., Marchot, P., De Pauw, E., Roberts, G.C., Frere, J.M. and Matagne, A. (2009) Positively Cooperative Binding of Zinc Ions to Bacillus cereus 569/H/9 β-Lactamase II Suggests that the Binuclear Enzyme Is the Only Relevant Form for Catalysis. Journal of Molecular Biology, 392, 1278-1291.
[95] Yang, Y., Rasmussen, B.A. and Bush, K. (1992) Biochemical Characterization of the Metallo-β-Lactamase CcrA from Bacteroides fragilis TAL3636. Antimicrobial Agents and Chemotherapy, 36, 1155-1157.
[96] Crowder, M.W., Wang, Z., Franklin, S., Zovinka, E.P. and Benkovic, S.J. (1996) Characterization of the Metal-Binding Sites of the β-Lactamase from Bacteroides fragilis. Biochemistry, 35, 12126-12132.
[97] Yanchak, M.P., Taylor, R.A. and Crowder, M.W. (2000) Mutational Analysis of Metallo-β-Lactamase CcrA from Bacteroides fragilis. Biochemistry, 39, 11330-11339.
[98] Park, H., Brothers, E.N. and Merz, K.M. (2005) Hybrid QM/MM and DFT Investigations of the Catalytic Mechanism and Inhibition of the Dinuclear Zinc Metallo-β-Lactamase CcrA from Bacteroides fragilis. Journal of the American Chemical Society, 127, 4232-4241.
[99] Hawk, M.J., Breece, R.M., Hajdin, C.E., Bender, K.M., Hu, Z.X., Costello, A.L., Bennett, B., Tierney, D.L. and Crowder, M.W. (2009) Differential Binding of Co(II) and Zn(II) to Metallo-β-Lactamase Bla2 from Bacillus anthracis. Journal of the American Chemical Society, 131, 10753-10762.
[100] Chen, R.F. (1967) Fluorescence Quantum Yields of Tryptophan and Tyrosine. Analytical Letters, 1, 35-42.
[101] Hunt, J.B., Neece, S.H. and Ginsburg, A. (1985) The Use of 4-(2-pyridylazo) Resorcinol in Studies of Zinc Release from Escherichia coli Aspartate Transcarbamoylase. Analytical Biochemistry, 146, 150-157.
[102] Eftink, M.R. (1991) Fluorescence Techniques for Studying Protein Structure. Methods of Biochemical Analysis, 35, 127-205.
[103] Simons, T.J.B. (1993) Measurement of Free Zn2+ Ion Concentration with the Fluorescent Probe Mag-fura-2 (furaptra). Journal of Biochemical and Biophysical Methods, 27, 25-37.
[104] McCall, K.A. and Fierke, C.A. (2000) Colorimetric and Fluorimetric Assays to Quantitate Micromolar Concentrations of Transition Metals. Analytical Biochemistry, 284, 307-315.
[105] Valladares, M.H., Felici, A., Weber, G., Adolph, H.W., Zeppezauer, M., Rossolini, G.M., Amicosante, G., Frère, J.M. and Galleni, M. (1997) Zn(II) Dependence of the Aeromonas hydrophila AE036 Metallo-β-Lactamase Activity and Stability. Biochemistry, 36, 11534-11541.
[106] Wommer, S., Rival, S., Heinz, U., Galleni, M., Frere, J.M., Franceschini, N., Amicosante, G., Rasmussen, B., Bauer, R. and Adolph, H.W. (2002) Substrate-Activated Zinc Binding of Metallo-β-Lactamases: Physiological Importance of the Mononuclear Enzymes. Journal of Biological Chemistry, 277, 24142-24147.
[107] Gonzàlez, J.M., Martìn, F.J., Costello, A.L., Tierney, D.L. and Vila, A.J. (2007) The Zn2 Position in Metallo-β-Lactamases Is Critical for Activity: A Study on Chimeric Metal Sites on a Conserved Protein Scaffold. Journal of Molecular Biology, 373, 1141-1156.
[108] Selevsek, N., Rival, S., Tholey, A., Heinzle, E., Heinz, U., Hemmingsen, L. and Adolph, H.W. (2009) Zinc Ion-Induced Domain Organization in Metallo-β-Lactamases: A Flexible “Zinc Arm” for Rapid Metal Ion Transfer? Journal of Biological Chemistry, 284, 16419-16431.
[109] Cricco, J.A., Orellano, E.G., Rasia, R.M., Ceccarelli, E.A. and Vila, A.J. (1999) Metallo-β-Lactamases: Does It Take Two to Tango? Coordination Chemistry Review, 190-192, 519-535.
[110] Badarau, A. and Page, M.I. (2008) Loss of Enzyme Activity during Turnover of the Bacillus cereus β-Lactamase Catalysed Hydrolysis of β-Lactams Due to Loss of Zinc Ion. Journal of Biological Inorganic Chemistry, 13, 919-928.
[111] Moran-Barrio, J., Gonzalez, J.M., Lisa, M.N., Costello, A.L., Peraro, M.D., Carloni, P., Bennett, B., Tierney, D.L., Limansky, A.S., Viale, A.M. and Vila, A.J. (2007) The Metallo-β-Lactamase GOB Is a Mono-Zn(II) Enzyme with a Novel Active Site. Journal of Biological Chemistry, 282, 18286-18293.
[112] Horsfall, L.E., Izougarhane, Y., Lassaux, P., Selevsek, N., Lienard, B.M.R., Poirel, L., Kupper, M.B., Hoffmann, K.M., Frere, J.-M., Galleni, M. and Bebrone, C. (2011) Broad Antibiotic Resistance Profile of the Subclass B3 Metallo-b-Lactamase GOB-1, a Di-Zinc Enzyme. FEBS Journal, 278, 1252-1263.

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