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Antimicrobial Agents and Chemotherapy, December 2007, p. 4401-4409, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00926-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Novel Plasmid-Mediated 16S rRNA m1A1408 Methyltransferase, NpmA, Found in a Clinically Isolated Escherichia coli Strain Resistant to Structurally Diverse Aminoglycosides{triangledown}

Jun-ichi Wachino,1,2 Keigo Shibayama,1 Hiroshi Kurokawa,1 Kouji Kimura,1 Kunikazu Yamane,1 Satowa Suzuki,1 Naohiro Shibata,1 Yasuyoshi Ike,2 and Yoshichika Arakawa1*

Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan,1 Department of Bacteriology and Bacterial Infection Control, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan2

Received 17 July 2007/ Returned for modification 9 August 2007/ Accepted 3 September 2007

We have isolated a multiple-aminoglycoside-resistant Escherichia coli strain, strain ARS3, and have been the first to identify a novel plasmid-mediated 16S rRNA methyltransferase, NpmA. This new enzyme shared a relatively low level of identity (30%) to the chromosomally encoded 16S rRNA methyltransferase (KamA) of Streptomyces tenjimariensis, an actinomycete aminoglycoside producer. The introduction of a recombinant plasmid carrying npmA could confer on E. coli consistent resistance to both 4,6-disubstituted 2-deoxystreptamines, such as amikacin and gentamicin, and 4,5-disubstituted 2-deoxystreptamines, including neomycin and ribostamycin. The histidine-tagged NpmA elucidated methyltransferase activity against 30S ribosomal subunits but not against 50S subunits and the naked 16S rRNA molecule in vitro. We further confirmed that NpmA is an adenine N-1 methyltransferase specific for the A1408 position at the A site of 16S rRNA. Drug footprinting data indicated that binding of aminoglycosides to the target site was apparently interrupted by methylation at the A1408 position. These observations demonstrate that NpmA is a novel plasmid-mediated 16S rRNA methyltransferase that provides a panaminoglycoside-resistant nature through interference with the binding of aminoglycosides toward the A site of 16S rRNA through N-1 methylation at position A1408.

* Corresponding author. Mailing address: Department of Bacterial Pathogenesis and Infection Control, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo 208-0011, Japan. Phone: 81-42-561-0771, ext. 500. Fax: 81-42-561-7173. E-mail: yarakawa{at}nih.go.jp

{triangledown} Published ahead of print on 17 September 2007.

Antimicrobial Agents and Chemotherapy, December 2007, p. 4401-4409, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00926-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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