[en] Various inhibitors of metallo-beta-lactamases have been reported; however, none are effective for all subgroups. Those that have been found to inhibit the enzymes of subclass B2 (catalytically active with one zinc) either contain a thiol (and show less inhibition towards this subgroup than towards the dizinc members of B1 and B3) or are inactivators behaving as substrates for the dizinc family members. The present work reveals that certain pyridine carboxylates are competitive inhibitors of CphA, a subclass B2 enzyme. X-ray crystallographic analyses demonstrate that pyridine-2,4-dicarboxylic acid chelates the zinc ion in a bidentate manner within the active site. Salts of these compounds are already available and undergoing biomedical testing for various nonrelated purposes. Pyridine carboxylates appear to be useful templates for the development of more-complex, selective, nontoxic inhibitors of subclass B2 metallo-beta-lactamases.
Disciplines :
Pharmacy, pharmacology & toxicology Microbiology
Author, co-author :
Horsfall, L. E.
Garau, G.
Lienard, B. M.
Dideberg, O.
Schofield, C. J.
Frere, J. A.
Galleni, Moreno ; Université de Liège - ULiège > Département des sciences de la vie > Macromolécules biologiques
Language :
English
Title :
Competitive inhibitors of the CphA metallo-beta-lactamase from Aeromonas hydrophila
Publication date :
June 2007
Journal title :
Antimicrobial Agents and Chemotherapy
ISSN :
0066-4804
eISSN :
1098-6596
Publisher :
Amer Soc Microbiology, Washington, United States - Washington
Ambler, R. P. 1980. The structure of β-lactamases. Philos. Trans. R. Soc. Lond. B 289:321-331.
Bebrone, C., C. Anne, K. De Vriendt, B. Devreese, G. M. Rossolini, J. van Beeumen, J. M. Frere, and M. Galleni. 2005. Dramatic broadening of the substrate profile of the Aeromonas hydrophila CphA metallo-β- lactamase by site-directed mutagenesis. J. Biol. Chem. 280:28195-28202.
Berman, H. M., J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I. N. Shindyalov, and P. E. Bourne. 2000. The Protein Data Bank. Nucleic Acids Res. 28:235-242.
Bush, K., G. A. Jacoby, and A. A. Medeiros. 1995. A functional classification scheme for β-lactamases and its correlation with molecular structure. Antimicrob. Agents Chemother. 39:1211-1233.
Cantor, C. R., and P. R. Schimmel. 1980. Biophysical chemistry. Part III: the behavior of biological macromolecules. W. H. Freeman and Company, New York, NY.
Carfl, A., S. Pares, E. Duee, M. Galleni, C. Duez, J. M. Frere, and O. Dideberg. 1995. The 3-D structure of a zinc metallo-β-lactamase from Bacillus cereus reveals a new type of protein fold. EMBO J. 14:4914-4921.
Collaborative Computational Project. 1994. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. Sect. D 50:760-763.
Concha, N. O., C. A. Janson, P. Rowling, S. Pearson, C. A. Cheever, B. P. Clarke, C. Lewis, M. Galleni, J. M. Frere, D. J. Payne, J. H. Bateson, and S. S. Abdel-Meguid. 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.
Cornish-Bowden, A. 2001. Fundamentals of enzyme kinetics. Portland Press Ltd., London, United Kingdom.
Derian, C. K., W. VanDusen, C. T. Przysiecki, P. N. Walsh, K. L. Bekner, R. J. Kaufman, and P. A. Friedman. 1989. Inhibitors of 2-ketoglutarate-dependent dioxygenases block aspartyl β-hydroxylation of recombinant human factor IX in several mammalian expression systems. J. Biol. Chem. 264:6615-6618.
Docquier, J. D., J. Lamotte-Brasseur, M. Galleni, G. Amicosante, J. M. Frere, and G. M. Rossolini. 2003. On functional and structural heterogeneity of VIM-type metallo-β-lactamases. J. Antimicrob. Chemother. 51:257-266.
Evans, G. W., C. I. Grace, and H. J. Votava. 1975. A proposed mechanism of zinc absorption in the rat. Am. J. Physiol. 228:501-505.
Evans, G. W., and P. E. Johnson. 1980. Characterization and quantitation of a zinc-binding ligand in human milk. Pediatr. Res. 14:876-880.
Fox, G. N., and Z. Sabovic. 1998. Chromium picolinate supplementation for diabetes mellitus. J. Fam. Pract. 46:83-86.
Franceschini, N., B. Caravelli, J.-D. Docquier, M. Galleni, J.-M. Frère, G. Amicosante, and G. M. Rossolini. 2000. Purification and biochemical characterization of the VIM-1 metallo-β-lactamase. Antimicrob. Agents Chemother. 44:3003-3007.
Frere, J. M. 1995. β-Lactamases and bacterial resistance to antibiotics. Mol. Microbiol. 16:385-395.
Galleni, M., J. Lamotte-Brasseur, G. M. Rossolini, J. Spencer, O. Dideberg, and J.-M. Frère. 2001. Standard numbering scheme for class B β-lactamases. Antimicrob. Agents Chemother. 45:660-663.
Garau, G., C. Bebrone, C. Anne, M. Galleni, J. M. Frere, and O. Dideberg. 2005. A metallo-β-lactamase enzyme in action: crystal structures of the monozinc carbapenemase CphA and its complex with biapenem. J. Mol. Biol. 345:785-795.
Ghuysen, J. M. 1991. Serine β-lactamases and penicillin-binding proteins. Annu. Rev. Microbiol. 45:37-67.
Hanauske-Abel, H. M. 1991. Prolyl-4-hydroxylase, a target enzyme for drug development. Design of suppressive agents and the in vitro effects of inhibitors and proinhibitors. J. Hepatol. 13(Suppl. 3):S8-S15.
Heinz, U., R. Bauer, S. Wommer, W. Meyer-Klaucke, C. Papamichaels, J. Bateson, and H. W. Adolph. 2003. Coordination geometries of metal ions in D- or L-captopril-inhibited metallo-β-lactamases. J. Biol. Chem. 278:20659-20666.
Hernandez-Valladares, M., A. Felici, G. Weber, H. W. Adolph, M. Zeppezauer, G. M. Rossolini, G. Amicsante, J. M. Frere, and M. Galleni. 1997. Zn(II) dependence of the Aeromonas hydrophila AE036 metallo-β-lactamase activity and stability. Biochemistry 36:11534-11541.
Hernandez-Valladares, M., M. Galleni, J. M. Frere, A. Felici, M. Perilli, N. Franceschini, G. M. Rossolini, A. Oratore, and G. Amicosante. 1996. Overproduction and purification of the Aeromonas hydrophila CphA metallo-β-lactamase expressed in Escherichia coli. Microb. Drug Resist. 2:253-256.
Hernandez-Valladares, M., M. Kiefer, U. Heinz, R. P. Soto, W. Meyer-Klaucke, H. F. Nolting, M. Zeppezauer, M. Galleni, J. M. Frere, G. M. Rossolini, G. Amicosante, and H. Adolph. 2000. Kinetic and spectroscopic characterization of native and metal-substituted β-lactamase from Aeromonas hydrophila AE036. FEBS Lett. 467:221-225.
Ivan, M., T. Haberberger, D. C. Gervasi, K. S. Michelson, V. Gunzler, K. Kondo, H. F. Yang, I. Sorokina, R. C. Conaway, J. W. Conaway, and G. Kaelin. 2002. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl. Acad. Sci. USA 99:13459-13464.
Jin, W., Y. Arakawa, H. Yasuzawa, T. Taki, R. Hashiguchi, K. Mitsutani, A. Shoga, Y. Yamaguchi, H. Kurosaki, N. Shibata, M. Ohta, and M. Goto. 2004. Comparative study of the inhibition of metallo-β-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group. Biol. Pharm. Bull. 27:851-856.
Jones, T. A., J. Y. Zou, S. W. Cowan, and M. Kjeldgaard. 1991. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr. Sect. A 47:110-119.
Kimura, S., Y. Ishii, and K. Yamaguchi. 2005. Evaluation of dipicolinic acid for the detection of IMP- or VIM-type metallo-β-lactamase- producing Pseudomonas aeruginosa clinical isolates. Diagn. Microbiol. Infect. Dis. 53: 241-244.
Kurosaki, H., Y. Yamaguchi, T. Higashi, K. Soga, S. Matsueda, H. Yumoto, S. Misumi, Y. Yamagata, Y. Arakawa, and M. Goto. 2005. Irreversible inhibition of metallo-β-lactamase (IMP-1) by 3-(3- mercaptopropionylsulfanyl)-propionic acid pentafluorophenyl ester. Angew. Chem. Int. Ed. 44:3861-3864.
Laraki, N., N. Franceschini, G. M. Rossolini, P. Santucci, C. Meunier, E. de Pauw, G. Amicosante, J. M. Frère, and M. Galleni. 1999. Biochemical characterization of the Pseudomonas aeruginosa 101/1477 metallo-β-lactamase IMP-1 produced by Escherichia coli. Antimicrob. Agents Chemother. 43: 902-906.
Matagne, A., A. Dubus, M. Galleni, and J. M. Frere. 1999. The β-lactamase cycle: a tale of selective pressure and bacterial ingenuity. Nat. Prod. Rep. 16:1-19.
Mercuri, P. S. 2002. Ph.D thesis. Université de Liège, Liège, Belgium.
Mercuri, P. S., F. Bouillenne, L. Boschi, J. Lamotte-Brasseur, G. Amicosante, B. Devreese, J. van Beeumen, J.-M. Frère, G. M. Rossolini, and M. Galleni. 2001. Biochemical characterization of the FEZ-1 metallo-β-lactamase of Legionella gonnanii ATCC 33297T produced in Escherichia coli. Antimicrob. Agents Chemother. 45:1254-1262.
Mollard, C., C. Moali, C. Papamicael, C. Damblon, S. Vessilier, G. Amicosante, C. J. Schofield, M. Galleni, J. M. Frere, and G. C. Roberts. 2001. Thiomandelic acid, a broad spectrum inhibitor of zinc β-lactamases: kinetic and spectroscopic studies. J. Biol. Chem. 276:45015-45023.
Paul-Soto, R., R. Bauer, J. M. Frere, M. Galleni, W. Meyer-Klaucke, H. Nolting, G. M. Rossolini, D. de Seny, M. Hernandez-Valladares, M. Zeppezauer, and H. W. Adolph. 1999. Mono- and binuclear Zn2+-β-lactamase. Role of the conserved cysteine in the catalytic mechanism. J. Biol. Chem. 274:13242-13249.
Paul-Soto, R., M. Hernandez-Valladares, M. Galleni, R. Bauer, M. Zeppezauer, J. M. Frere, and H. W. Adolph. 1998. Mono- and binuclear Zn-β-lactamase from Bacteroides fragilis: catalytic and structural roles of the zinc ions. FEBS Lett. 438:137-140.
Reading, S. A. 1996. Chromium picolinate. J. Fla. Med. Assoc. 83:29-31.
Sharir, M., and T. J. Zimmerman. 1993. In vitro inhibition of collagen formation by 2,4-pyridine dicarboxylate and minoxidil in rabbit corneal fibroblasts. Curr. Eye Res. 12:553-559.
Siemann, S., A. J. Clarke, T. Viswanatha, and G. I. Dmitrienko. 2002. Thiols as classical and slow-binding inhibitors of IMP-1 and other binuclear metallo-β-lactamases. Biochemistry 42:1673-1683.
Siemann, S., D. P. Evanoff, L. Marrone, A. J. Clarke, T. Viswanatha, and G. I. Dmitrienko. 2002. N-arylsulfonyl hydrazones as inhibitors of IMP-1 metallo-β-lactamase. Antimicrob. Agents Chemother. 46:2450-2457.
Tschank, G., D. G. Brocks, K. Engelbart, J. Mohr, E. Baader, V. Gunzler, and H. M. Hanauske-Abel. 1991. Inhibition of prolyl hydroxylation and procollagen processing in chick-embryo calvaria by a derivative of pyridine-2,4-dicarboxylate. Characterization of the diethyl ester as a proinhibitor. Biochem. J. 275:469-176.
Ullah, J. H., T. R. Walsh, I. A. Taylor, D. C. Emery, C. S. Verma, S. J. Gamblin, and J. Spencer. 1998. The crystal structure of the L1 metallo-β-lactamase from Stenotrophomonas maltophilia at 1.7 Å resolution. J. Mol. Biol. 284:125-136.
Vincent, J. B. 2003. The potential value and toxicity of chromium picolinate as a nutritional supplement, weight loss agent and muscle development agent. Sports Med. 33:213-230.
Zervosen, A., M. H. Valladares, B. Devreese, C. Prosperi-Meys, H. W. Adolph, P. S. Mercuri, M. Vanhove, G. Amicosante, J. van Beeumen, J. M. Frere, and M. Galleni. 2001. Inactivation of Aeromonas hydrophila metallo-β-lactamase by cephamycins and moxalactam. Eur. J. Biochem. 268:3840-3850.