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Antimicrobial Agents and Chemotherapy, June 2002, p. 2056-2057, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.2056-2057.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

The Extended-Spectrum K1 ß-Lactamase from Klebsiella oxytoca SC 10,436 Is a Member of the blaOXY-2 Family of Chromosomal Klebsiella Enzymes


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LETTER
 
Bacteria in the genus Klebsiella have had a curious history of multiple names, together with multiple names for the chromosomal ß-lactamases they produce. These enzymes have played a major role in the development of new classes of ß-lactams but are less widely recognized than some of the more prominent TEM or SHV plasmid-encoded ß-lactamases.

Within this family of enzymes is the K1 ß-lactamase, first identified from a sick child infected with Klebsiella aerogenes (Klebsiella pneumoniae) 1082E in Glasgow, Scotland (8, 9). This enzyme is also known in the literature as the chromosomal enzyme from K. aerogenes NCTC 418 that Beecham scientists used to characterize the ß-lactamase inhibitor clavulanic acid from Streptomyces clavuligerus fermentation broths (3). The K1 ß-lactamase from K. pneumoniae SC 10,436, a strain documented as originating from K. aerogenes 1082E, became a pivotal enzyme in the Squibb monobactam program, based on the observation that it hydrolyzed many monobactams more rapidly than cephalosporins or penicillins; aztreonam was selected for clinical development because it was the most ß-lactamase-stable monobactam in the Squibb library in 1980 (11). At that time, the K1 ß-lactamase was the only bacterial enzyme that hydrolyzed aztreonam at a relative rate that was at least 10% greater than that for cephaloridine, hence its designation as the first extended-spectrum ß-lactamase in the functional ß-lactamase classification by Bush in 1989 (4). In 1986, this strain was renamed Klebsiella oxytoca SC 10,436 based on changes in Klebsiella nomenclature (2).

During the 1990s, systematic analyses of K. oxytoca clinical isolates have revealed two distinct groups of K1 ß-lactamase genes, blaOXY-1 and blaOXY-2. These groups have approximately 87% sequence identity (7). However, when this analysis was completed, no historical K1-producing strain was included. In this report, we describe the identification of the K1 bla gene from K. oxytoca SC 10,436.

The coding and promoter regions were amplified using the primers OXY-A (5'-TCGGTAACTGTGACGGGA-3') and OXY-B (5'-CCGAATTTCGGGAAGCCA-3') and then sequenced with an automated cycle-sequencing system.

The sequence analysis (GenBank accession no. AY055205) showed that the gene encoding K1 from strain SC 10,436 is very similar to the blaOXY-2 group. However, it differs from the reference blaOXY-2-1 gene (GenBank accession no. Z49084) by five mutations. Two of these mutations are silent (A603G and A855G) while three of the mutations (G94A, G622A, and G790A) are responsible for the following amino acid substitutions: Gly20Ser located in the sequence signal and Asp197Asn and Asp255Asn located in the mature protein. As indicated in Table 1, these three substitutions have been previously published but not in the same association as found in K1 from strain SC 10,436 (6, 10).


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  		TABLE 1. Amino acid substitutions in K1 protein of Klebsiella oxytoca strain SC 10,436 compared with previously published K1 OXY-2

In addition to the mutations in the coding gene, two others were observed in the promoter region: GATAGT -> GATAAT (-10 region) and TTGTCA -> TTGACA (-35 region). The association of these two mutations has been previously shown as creating the strongest promoter among those tested after having been cloned upstream of the cat gene (5). The presence of such a promoter explains the increased hydrolytic activity against monobactams that is observed in the K1-producing strain SC 10,436.


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REFERENCES
 
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  1. Ambler, R. P., A. F. W. Coulson, J. M. Frère, J. M. Ghuysen, B. Joris, M. Forsman, R. C. Levesque, G. Tiraby, and S. G. Waley. 1991. A standard numbering scheme for the class A ß-lactamases. Biochem. J. 276:269-270.[Medline]
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  2. Arakawa, Y., M. Ohta, N. Kido, M. Mori, H. Ito, T. Komatsu, Y. Fujii, and N. Kato. 1989. Chromosomal beta-lactamase of Klebsiella oxytoca, a new class A enzyme that hydrolyzes broad-spectrum ß-lactam antibiotics. Antimicrob. Agents Chemother. 33:63-70.[Abstract/Free Full Text]
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  3. Brown, A. G., D. Butterworth, M. Cole, G. Hanscomb, J. D. Hood, C. Reading, and G. N. Rolinson. 1976. Naturally occurring b-lactamase inhibitors with antibacterial activity. J. Antibiot. 29:668-669.[Medline]
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  4. Bush, K. 1989. Classification of beta-lactamases: groups 1, 2a, 2b, and 2b'. Antimicrob. Agents Chemother. 33:264-270.[Free Full Text]
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  5. Fournier, B., A. Gravel, D. C. Hooper, and P. H. Roy. 1999. Strength and regulation of the different promoters for chromosomal beta-lactamases of Klebsiella oxytoca. Antimicrob. Agents Chemother. 43:850-855.[Abstract/Free Full Text]
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  6. Fournier, B., and P. H. Roy. 1997. Variability of chromosomally encoded beta-lactamases from Klebsiella oxytoca. Antimicrob. Agents Chemother. 41:1641-1648.[Abstract/Free Full Text]
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  7. Fournier, B., P. H. Roy, P. H. Lagrange, and A. Philippon. 1996. Chromosomal ß-lactamase genes of Klebsiella oxytoca are divided into two main groups, blaOXY-1 and blaOXY- 2. Antimicrob. Agents Chemother. 40:454-459.[Abstract/Free Full Text]
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  8. Gheorghiu, R., M. Yuan, L. M. C. Hall, and D. M. Livermore. 1997. Bases of variation in resistance to beta-lactams in Klebsiella oxytoca isolates hyperproducing K1 beta-lactamase. J. Antimicrob. Chemother. 40:533-541.[Abstract/Free Full Text]
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  9. Marshall, M. J., G. W. Ross, K. V. Chanter, and A. M. Harris. 1972. Comparison of the substrate specificities of the b-lactamases from Klebsiella aerogenes 1082E and Enterobacter cloacae P99. Appl. Microbiol. 23:765-769.[Medline]
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  10. Sirot, D., R. Labia, P. Pouedras, C. Chanal-Claris, C. Cerceau, and J. Sirot. 1998. Inhibitor-resistant OXY-2 derived beta-lactamase produced by Klebsiella oxytoca. Antimicrob. Agents Chemother. 42:2184-2187.[Abstract/Free Full Text]
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  11. Sykes, R. B., D. P. Bonner, K. Bush, and N. H. Georgopapadakou. 1982. Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria. Antimicrob. Agents Chemother. 21:85-92.[Abstract/Free Full Text]
Sophie A. Granier
Véronique Leflon-Guibout
Marie-Hélène Nicolas-Chanoine*
Service de Microbiologie-Hygiène
Microbiology Department
Hôpital Ambroise Paré AP-HP
9 avenue Charles de Gaulle
Université Versailles-Saint-Quentin-en-Yvelines-UFR
Médicale Paris-Ile-de-France-Ouest
Boulogne-Billancourt, France

Karen Bush
Johnson & Johnson Pharmaceutical Research &
 Development
Raritan, New Jersey

Fred W. Goldstein
Laboratoire de Microbiologie Médicale
Fondation Hôpital Saint-Joseph
Paris, France

* Phone: 33-1-49 09 55 40
Fax: 33-1-49 09 59 21
E-mail: marie-helene.nicolas-chanoine{at}apr.ap-hop-paris.fr

Antimicrobial Agents and Chemotherapy, June 2002, p. 2056-2057, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.2056-2057.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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