Contribution of beta-lactamase and PBP amino acid substitutions to amoxicillin/clavulanate resistance in beta-lactamase-positive, amoxicillin/clavulanate-resistant Haemophilus influenzae

J Antimicrob Chemother. 2003 Dec;52(6):1018-21. doi: 10.1093/jac/dkg474. Epub 2003 Oct 29.

Abstract

The roles of beta-lactamase and alterations in penicillin-binding protein in the development of amoxicillin and amoxicillin/clavulanate resistance in two beta-lactamase-positive, amoxicillin/clavulanate-resistant (BLPACR) strains of Haemophilus influenzae were investigated. Seven beta-lactamase-negative, ampicillin-resistant (BLNAR) strains were also studied for comparison of their resistance mechanisms. All strains had been recovered from patients in Japan. The TEM type beta-lactamase of the two BLPACR strains had 100% homology with the amino acid sequences of published TEM-1 beta-lactamase, showing that amoxicillin/clavulanate resistance was not associated with mutations in this beta-lactamase. However, these strains, as well as the seven BLNAR strains, had multiple mutations in ftsI, which encodes penicillin binding protein 3 (PBP3). The transformation of H. influenzae Rd strain with amplified ftsI genes from two BLPACR and two BLNAR strains enabled the selection of amoxicillin/clavulanate-resistant transformants with the same mutations as their parent strains. We concluded that amoxicillin/clavulanate resistance in the two BLPACR strains was due to changes in PBP3. The possibility of the presence of an extended spectrum beta-lactamase was excluded in the BLPACR strains studied.

MeSH terms

  • Amino Acid Substitution / genetics*
  • Amoxicillin-Potassium Clavulanate Combination / pharmacology*
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • DNA, Bacterial / genetics
  • Drug Resistance, Bacterial
  • Drug Therapy, Combination / pharmacology*
  • Haemophilus Infections / microbiology
  • Haemophilus influenzae / drug effects*
  • Haemophilus influenzae / genetics*
  • Hexosyltransferases / genetics*
  • Hexosyltransferases / metabolism*
  • Microbial Sensitivity Tests
  • Muramoylpentapeptide Carboxypeptidase / genetics*
  • Muramoylpentapeptide Carboxypeptidase / metabolism*
  • Mutation / genetics
  • Mutation / physiology
  • Penicillin-Binding Proteins
  • Peptidyl Transferases / genetics*
  • Peptidyl Transferases / metabolism*
  • Transformation, Bacterial
  • beta-Lactamases / genetics*
  • beta-Lactamases / metabolism*

Substances

  • Bacterial Proteins
  • Carrier Proteins
  • DNA, Bacterial
  • Penicillin-Binding Proteins
  • Amoxicillin-Potassium Clavulanate Combination
  • Peptidyl Transferases
  • Hexosyltransferases
  • Muramoylpentapeptide Carboxypeptidase
  • beta-Lactamases