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Antimicrobial Agents and Chemotherapy, June 2001, p. 1693-1699, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1693-1699.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Association of Amino Acid Substitutions in Penicillin-Binding Protein 3 with beta -Lactam Resistance in beta -Lactamase-Negative Ampicillin-Resistant Haemophilus influenzae

Kimiko Ubukata,1,2,* Yumi Shibasaki,1 Kentarou Yamamoto,1 Naoko Chiba,1 Keiko Hasegawa,1 Yasuo Takeuchi,1 Keisuke Sunakawa,3 Matsuhisa Inoue,4 and Masatoshi Konno5

Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morookacho, Kohoku-ku, Yokohama,1 Institute of Microbial Chemistry, Kamiohsaki, Shinagawa-ku,2 and Teikyo University School of Medicine,5 Tokyo, and Department of Infectious Diseases3 and Department of Bacteriology,4 School of Medicine, Kitasato University, Kitasato, Sagamihara, Japan

Received 30 November 2000/Returned for modification 23 February 2001/Accepted 12 March 2001

The affinity of [3H]benzylpenicillin for penicillin-binding protein (PBP) 3A was reduced in 25 clinical isolates of beta -lactamase-negative ampicillin (AMP)-resistant (BLNAR) Haemophilus influenzae for which the AMP MIC was >= 1.0 µg/ml. The affinities of PBP 3B and PBP 4 were also reduced in some strains. The sequences of the ftsI gene encoding the transpeptidase domain of PBP 3A and/or PBP 3B and of the dacB gene encoding PBP 4 were determined for these strains and compared to those of AMP-susceptible Rd strains. The BLNAR strains were classified into three groups on the basis of deduced amino acid substitutions in the ftsI gene, which is thought to be involved in septal peptidoglycan synthesis. His-517, near the conserved Lys-Thr-Gly (KTG) motif, was substituted for Arg-517 in group I strains (n = 9), and Lys-526 was substituted for Asn-526 in group II strains (n = 12). In group III strains (n = 4), three residues (Met-377, Ser-385, and Leu-389), positioned near the conserved Ser-Ser-Asn (SSN) motif, were replaced with Ile, Thr, and Phe, respectively, in addition to the replacement with Lys-526. The MICs of cephem antibiotics with relatively high affinities for PBP 3A and PBP 3B were higher than those of AMP and meropenem for group III strains. The MICs of beta -lactams for H. influenzae transformants into which the ftsI gene from BLNAR strains was introduced were as high as those for the donors, and PBP 3A and PBP 3B showed decreased affinities for beta -lactams. There was no clear relationship between 7-bp deletions in the dacB gene and AMP susceptibility. Even though mutations in another gene(s) may be involved in beta -lactam resistance, these data indicate that mutations in the ftsI gene are the most important for development of resistance to beta -lactams in BLNAR strains.

* Corresponding author. Mailing address: Kimiko Ubukata, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morookacho, Kohoku-ku, Yokohama, 222-8567, Japan. Phone: 81-45-545-3106. Fax: 81-45-545-3193. E-mail: kimiko_ubukata{at}meiji.co.jp.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1693-1699, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1693-1699.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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