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Antimicrobial Agents and Chemotherapy, May 2002, p. 1516-1521, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1516-1521.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antagonism between Aminoglycosides and ß-Lactams in a Methicillin-Resistant Staphylococcus aureus Isolate Involves Induction of an Aminoglycoside-Modifying Enzyme

Takashi Ida,¹ Ryoichi Okamoto,¹ Masato Nonoyama,¹ Kazuhiko Irinoda,¹ Mizuyo Kurazono,² and Matsuhisa Inoue^1*

Department of Microbiology, Kitasato University School of Medicine, 1-15-1 Kitasato Sagamihara Kanagawa 228-8555,¹ Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan²

Received 16 August 2001/ Returned for modification 7 November 2001/ Accepted 24 January 2002

We encountered three clinical isolates of methicillin-resistant Staphylococcus aureus which were susceptible to netilmicin and arbekacin in the absence of ß-lactam antibiotics but which were resistant to them in the presence of ß-lactam antibiotics. One of these strains, KU5801, was used to further investigate the antagonism between aminoglycosides and ß-lactam antibiotics. ß-Lactam antibiotics induced bacterial synthesis of aminoglycoside-6'-N-acetyltransferase and 2"-O-phosphotransferase [AAC(6')-APH(2")] in association with decreased antimicrobial activities of aminoglycosides. A 14.4-kb EcoRI fragment that included the genes that control for ß-lactam-inducible aminoglycoside resistance was cloned from a 31-kb conjugative plasmid present in KU5801. Restriction fragment mapping and PCR analysis suggested that a Tn4001-like element containing a gene encoding AAC(6')-APH(2") was located downstream from a truncated blaZ gene. The DNA sequence between blaR1 and a Tn4001-like element was determined. The Tn4001-IS257 hybrid structure was cointegrated into the blaZ gene, and the typical sequences for the termination of transcription were not found between these regions. We deduced that antagonism of aminoglycosides by ß-lactam antibiotics in isolate KU5801 involved transcription of the aac(6')-Ie-aph(2")-Ia gene under the influence of the system regulating penicillinase production.

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* Corresponding author. Mailing address: Department of Microbiology, Kitasato University School of Medicine, 1-15-1 Kitasato Sagamihara Kanagawa 228-8555, Japan. Phone: 81-42-778-9355. Fax: 81-42-778-9350. E-mail: matsu{at}kitasato-u.ac.jp.

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Antimicrobial Agents and Chemotherapy, May 2002, p. 1516-1521, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1516-1521.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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