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Chemical Compound Review

AC1NRCHM     (2R)-2-[(1S)-2-oxo-1-(2- thiophen-2...

Synonyms: DB04742
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Disease relevance of Nitrocefin

  • Immunofluorescence microscopy, the accessibility of the fusion protein to externally added proteases, and the rates of hydrolysis of nitrocefin and penicillin G by whole cells demonstrated that a substantial fraction (20-30%) of the beta-lactamase domain of the fusion protein was exposed on the external surface of E. coli [1].
  • The catalytic mechanism of metallo-beta-lactamase from Bacteroides fragilis, a dinuclear Zn(II)-containing enzyme responsible for multiple antibiotic resistance, has been investigated by using nitrocefin as a substrate [2].
  • Hydrolysis of the chromogenic beta-lactam nitrocefin by periplasmic beta-lactamase in intact Pseudomonas aeruginosa cells was used to assess the influence of various compounds on the permeability of the P. aeruginosa outer membrane [3].
  • The reaction of nitrocefin with metallo-beta-lactamase L1 from Stenotrophomonas maltophilia was studied using rapid-scan and stopped-flow ultraviolet-visible (UV-vis) studies in an effort to discern the kinetic mechanism used by L1 to hydrolyze penicillins and cephalosporins [4].
  • The prevalence of beta-lactamase-producing bacteria in subgingival plaque from patients with refractory periodontitis in Norway was assessed by the chromogenic nitrocefin method. beta-Lactamase activity was detected in 68% of the patients [5].

Psychiatry related information on Nitrocefin


High impact information on Nitrocefin

  • In cells grown at 24 degrees C the localization of beta-lactamase on the cell surface was almost quantitative (greater than 80% of the enzymatically active protein was exposed to the extracellular fluid) as determined by nitrocefin and penicillin G hydrolysis and trypsin accessibility [1].
  • In the case of D120(81)E, the nitrocefin hydrolysis product, which shows a maximum absorption at 460 nm, was bound to D120(81)E in the protonated form [7].
  • Additionally, the 2.4-angstroms structure of the acyl-enzyme complex of R39 with nitrocefin reveals the absence of active site conformational change upon binding the beta-lactams [8].
  • We suggest, therefore, that the mechanism of hydrolysis of nitrocefin by binuclear metallo-beta-lactamases may be atypical and that cleavage of the beta-lactam amide bond is the rate-determining step for breakdown of the majority of beta-lactam substrates by the L1 enzyme [9].
  • The 200 ps QM/MM simulation of the CcrA enzyme in complex with nitrocefin shows that the substrate beta-lactam moiety is directed toward the active site dizinc center through the interactions of aminocarbonyl and carboxylate groups with the two active site zinc ions and the two conserved residues, Lys167 and Asn176 [10].

Chemical compound and disease context of Nitrocefin

  • It has been presumed that there are just two beta-lactamases in the motile Aeromonas species, a carbapenemase and a cephalosporinase, based on the premise that all beta-lactamases can be detected by hydrolysis of the chromogenic cephalosporin, nitrocefin [11].
  • Plasmid-encoded beta-lactamases were rare in Klebsiella spp., being found in six (7.5%) isolates of K. pneumoniae and in none of the K. oxytoca. beta-Lactamase activities were relatively low (< 100 nmoles nitrocefin hydrolysed per minute per mg of protein) and ampicillin MICs were < or = 128 mg/L for most isolates of both species [12].
  • A substrate, pyridine-2-azo-p-dimethylaniline cephalosporin (PADAC; Diagnostic Pasteur, Marnes-La-Coquette, France), for detection of penicillinase-producing Neisseria gonorrhoeae (PPNG) on isolated colonies grown on agar was compared with the nitrocefin reference test (Cefinase; Biomerieux, Marcy l'Etoile, France) [13].
  • Extended X-ray absorption fine structure studies of the metallo-beta-lactamase L1 from Stenotrophomonas maltophilia containing 1 and 2 equiv of Zn(II) and containing 2 equiv of Zn(II) plus hydrolyzed nitrocefin are presented [14].
  • Twenty micromolar tazobactam inhibited total beta-lactamase activity (as measured by nitrocefin hydrolysis rates) by greater than 75% against all isolates tested: in 11 of 13 E. coli isolates, total beta-lactamase activity was inhibited by 90% [15].

Biological context of Nitrocefin

  • Using nitrocefin, a chromogenic beta-lactam, we confirmed the correlation between PBP 2a' precipitation and its beta-lactam-dependent enzymatic acylation by monitoring the absorbance associated with the precipitate [16].
  • IC50 values (microM) with nitrocefin, piperacillin and penicillin G substrates (concentrations 20, 100 and 20 microM, respectively) were > 1000, 7, 3.5 (clavulanate); > 1000, 300, 59 (sulbactam), > 1000, 29, 7.7 (tazobactam); 0.0004, 0.001, 0.0018 (BRL 42715) [17].
  • The kinetics of the La(3+)-catalyzed methanolysis of N-phenyl-beta-lactam (2) and N-p-nitrophenyl-beta-lactam (3) as well as that of nitrocefin (1) were studied at 25 degrees C under buffered conditions [18].
  • Cefoxitin susceptibility was performed using an agar dilution method, beta-lactamase production by using a nitrocefin method, and plasmid extraction by using a commercial kit [19].
  • Three different beta-lactamase substrate profiles were identified in 95 isolates of coagulase-negative staphylococci (CNS), of 57 different phenotypes, from 16 orthopaedic inpatients and staff members in one ward, by applying a bacterial whole-cell assay based on the hydrolysis of cefazolin, cephaloridine and nitrocefin [20].

Anatomical context of Nitrocefin


Associations of Nitrocefin with other chemical compounds


Gene context of Nitrocefin

  • Testing beta-lactamase production with nitrocefin was more predictive for the presence of the blaZ gene than the agar dilution method and the results of the former agreed highly with the presence of the blaZ gene in the isolates [30].
  • Compounds 3a-c, 7a-c were able to inhibit either TEM-1 (a Class A enzyme, from Escherichia coli) or P-99 (a Class C enzyme, from E. cloacae), or both enzymes, when tested in competition experiments using nitrocefin as the reporter substrate [31].
  • Using a nitrocefin competition assay, I determined the relative substrate affinity index (RSAI) values of nine clinically significant beta-lactamase enzymes against a range of beta-lactams [32].
  • This was particularly true for the bile-resistant or Bacteroides fragilis group. beta-Lactamase production was detected in 82% of the bacteroides with the nitrocefin test [33].
  • Familial mutations and zinc stoichiometry determine the rate-limiting step of nitrocefin hydrolysis by metallo-beta-lactamase from Bacteroides fragilis [34].

Analytical, diagnostic and therapeutic context of Nitrocefin


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  2. On the mechanism of the metallo-beta-lactamase from Bacteroides fragilis. Wang, Z., Fast, W., Benkovic, S.J. Biochemistry (1999) [Pubmed]
  3. Compounds which increase the permeability of the Pseudomonas aeruginosa outer membrane. Hancock, R.E., Wong, P.G. Antimicrob. Agents Chemother. (1984) [Pubmed]
  4. Kinetic mechanism of metallo-beta-lactamase L1 from Stenotrophomonas maltophilia. McManus-Munoz, S., Crowder, M.W. Biochemistry (1999) [Pubmed]
  5. Antibiotic resistance in bacteria isolated from subgingival plaque in a norwegian population with refractory marginal periodontitis. Handal, T., Caugant, D.A., Olsen, I. Antimicrob. Agents Chemother. (2003) [Pubmed]
  6. Development, characterization, and initial evaluations of S1. A new chromogenic cephalosporin for beta-lactamase detection. Sutton, L.D., Biedenbach, D.J., Yen, A., Jones, R.N. Diagn. Microbiol. Infect. Dis. (1995) [Pubmed]
  7. Probing the role of Asp-120(81) of metallo-beta-lactamase (IMP-1) by site-directed mutagenesis, kinetic studies, and X-ray crystallography. Yamaguchi, Y., Kuroki, T., Yasuzawa, H., Higashi, T., Jin, W., Kawanami, A., Yamagata, Y., Arakawa, Y., Goto, M., Kurosaki, H. J. Biol. Chem. (2005) [Pubmed]
  8. Crystal structure of the Actinomadura R39 DD-peptidase reveals new domains in penicillin-binding proteins. Sauvage, E., Herman, R., Petrella, S., Duez, C., Bouillenne, F., Frère, J.M., Charlier, P. J. Biol. Chem. (2005) [Pubmed]
  9. Novel mechanism of hydrolysis of therapeutic beta-lactams by Stenotrophomonas maltophilia L1 metallo-beta-lactamase. Spencer, J., Clarke, A.R., Walsh, T.R. J. Biol. Chem. (2001) [Pubmed]
  10. Hybrid QM/MM and DFT investigations of the catalytic mechanism and inhibition of the dinuclear zinc metallo-beta-lactamase CcrA from Bacteroides fragilis. Park, H., Brothers, E.N., Merz, K.M. J. Am. Chem. Soc. (2005) [Pubmed]
  11. The 'hidden' carbapenemase of Aeromonas hydrophila. Hayes, M.V., Thomson, C.J., Amyes, S.G. J. Antimicrob. Chemother. (1996) [Pubmed]
  12. Rarity of transferable beta-lactamase production by Klebsiella species. Leung, M., Shannon, K., French, G. J. Antimicrob. Chemother. (1997) [Pubmed]
  13. Evaluation of a method for rapid detection of penicillinase-producing Neisseria gonorrhoeae in urethral exudates. Herve, V.M., Georges, A.J., Massanga, M., Martin, P.M. J. Clin. Microbiol. (1989) [Pubmed]
  14. Site-selective binding of Zn(II) to metallo-beta-lactamase L1 from Stenotrophomonas maltophilia. Costello, A., Periyannan, G., Yang, K.W., Crowder, M.W., Tierney, D.L. J. Biol. Inorg. Chem. (2006) [Pubmed]
  15. Exploring the effectiveness of tazobactam against ceftazidime resistant Escherichia coli: insights from the comparison between susceptibility testing and beta-lactamase inhibition. Bethel, C.R., Hujer, A.M., Helfand, M.S., Bonomo, R.A. FEMS Microbiol. Lett. (2004) [Pubmed]
  16. Specific interaction between beta-lactams and soluble penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus: development of a chromogenic assay. Roychoudhury, S., Kaiser, R.E., Brems, D.N., Yeh, W.K. Antimicrob. Agents Chemother. (1996) [Pubmed]
  17. Characterization of a beta-lactamase from Clostridium clostridioforme. Appelbaum, P.C., Spangler, S.K., Pankuch, G.A., Philippon, A., Jacobs, M.R., Shiman, R., Goldstein, E.J., Citron, D.M. J. Antimicrob. Chemother. (1994) [Pubmed]
  18. La3+-catalyzed methanolysis of N-aryl-beta-lactams and nitrocefin. Montoya-Pelaez, P.J., Gibson, G.T., Neverov, A.A., Brown, R.S. Inorganic chemistry. (2003) [Pubmed]
  19. Plasmid-Related Resistance to Cefoxitin in Species of the Bacteroides fragilis Group Isolated from Intestinal Tracts of Calves. Dos Santos Almeida, F., Avila-Campos, M.J. Curr. Microbiol. (2006) [Pubmed]
  20. beta-Lactamase substrate profiles of coagulase-negative skin staphylococci from orthopaedic inpatients and staff members. Thore, M. J. Hosp. Infect. (1992) [Pubmed]
  21. High-level beta-lactamase activity in sputum samples from cystic fibrosis patients during antipseudomonal treatment. Giwercman, B., Meyer, C., Lambert, P.A., Reinert, C., Høiby, N. Antimicrob. Agents Chemother. (1992) [Pubmed]
  22. Mechanisms responsible for reduced susceptibility to imipenem in Bacteroides fragilis. Edwards, R., Greenwood, D. J. Antimicrob. Chemother. (1996) [Pubmed]
  23. Rapid detection in spinal fluid of beta-lactamase produced by ampicillin-resistant Haemophilus influenzae. Boughton, W.H. J. Clin. Microbiol. (1982) [Pubmed]
  24. beta-Lactamases are absent from Archaea (archaebacteria). Martin, H.H., König, H. Microb. Drug Resist. (1996) [Pubmed]
  25. Investigation of beta-Lactamases in clinical isolates of Staphylococcus aureus for further explanation of borderline methicillin resistance. Keseru, J.S., Gál, Z., Barabás, G., Benko, I., Szabó, I. Chemotherapy. (2005) [Pubmed]
  26. Creation of an allosteric enzyme by domain insertion. Guntas, G., Ostermeier, M. J. Mol. Biol. (2004) [Pubmed]
  27. Cryoenzymology of Bacillus cereus beta-lactamase II. Bicknell, R., Waley, S.G. Biochemistry (1985) [Pubmed]
  28. Structure and kinetics of the beta-lactamase mutants S70A and K73H from Staphylococcus aureus PC1. Chen, C.C., Smith, T.J., Kapadia, G., Wäsch, S., Zawadzke, L.E., Coulson, A., Herzberg, O. Biochemistry (1996) [Pubmed]
  29. Inactivation of cefoxitin and moxalactam by Bacteroides bivius beta-lactamase. Malouin, F., Fijalkowski, C., Lamothe, F., Lacroix, J.M. Antimicrob. Agents Chemother. (1986) [Pubmed]
  30. Comparison of phenotypic and genotypic detection of penicillin G resistance of Staphylococcus aureus isolated from bovine intramammary infection. Haveri, M., Suominen, S., Rantala, L., Honkanen-Buzalski, T., Pyörälä, S. Vet. Microbiol. (2005) [Pubmed]
  31. Synthesis of new C-6 alkyliden penicillin derivatives as beta-lactamase inhibitors. Di Giacomo, B., Tarzia, G., Bedini, A., Gatti, G., Bartoccini, F., Balsamini, C., Tontini, A., Baffone, W., Di Modugno, E., Felici, A. Farmaco (2002) [Pubmed]
  32. Relative substrate affinity index values: a method for identification of beta-lactamase enzymes and prediction of successful beta-lactam therapy. James, R. J. Clin. Microbiol. (1983) [Pubmed]
  33. National Committee for Clinical Laboratory Standards agar dilution susceptibility testing of anaerobic gram-negative bacteria. Brown, W.J. Antimicrob. Agents Chemother. (1988) [Pubmed]
  34. Familial mutations and zinc stoichiometry determine the rate-limiting step of nitrocefin hydrolysis by metallo-beta-lactamase from Bacteroides fragilis. Fast, W., Wang, Z., Benkovic, S.J. Biochemistry (2001) [Pubmed]
  35. Analysis of the importance of the metallo-beta-lactamase active site loop in substrate binding and catalysis. Moali, C., Anne, C., Lamotte-Brasseur, J., Groslambert, S., Devreese, B., Van Beeumen, J., Galleni, M., Frère, J.M. Chem. Biol. (2003) [Pubmed]
  36. Detection of extended-spectrum beta-lactamases in clinical isolates of Pseudomonas aeruginosa. Jiang, X., Zhang, Z., Li, M., Zhou, D., Ruan, F., Lu, Y. Antimicrob. Agents Chemother. (2006) [Pubmed]
  37. In vitro evaluation of pyridine-2-azo-p-dimethylaniline cephalosporin, a new diagnostic chromogenic reagent, and comparison with nitrocefin, cephacetrile, and other beta-lactam compounds. Jones, R.N., Wilson, H.W., Novick, W.J. J. Clin. Microbiol. (1982) [Pubmed]
  38. Natural antibiotic susceptibility of Ewingella americana strains. Stock, I., Sherwood, K.J., Wiedemann, B. Journal of chemotherapy (Florence, Italy) (2003) [Pubmed]
  39. Detection of beta lactamase in sputum. Connell, C., Aspinall, S., Corkill, J. J. Clin. Pathol. (1994) [Pubmed]
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