JAC Advance Access originally published online on January 28, 2003
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Journal of Antimicrobial Chemotherapy (2003) 51, 523-530
© 2003 The British Society for Antimicrobial Chemotherapy
Cefuroxime resistance in non-ß-lactamase Haemophilus influenzae is linked to mutations in ftsI
1 Bristol Centre of Antimicrobial Research and Evaluation (BCARE), Department of Pathology and Microbiology, University of Bristol, Bristol BS8 1TD; 2 Department of Medical Microbiology, Southmead Hospital, North Bristol NHS Trust, Bristol BS8 1TD, UK
Received 13 September 2002; returned 15 October 2002; revised 25 November 2002; accepted 26 November 2002
The penicillin binding protein (PBP) genes dacA, dacB and ftsI from 14 cefuroxime-resistant (CXMR) isolates and three clinical isolates with low CXM MIC for non-ß-lactamase-producing Haemophilus influenzae type b were molecularly characterized. One strain, 5788, was used to transform H. influenzae Rd to CXMR for direct comparison of the pbps in the same genetic background. No obvious mutations in the dacA and dacB gene products could be associated with CXMR. One amino acid substitution in the ftsI gene product in particular, S357N, could give rise to CXMR. Sequence analysis from the CXMR transformants also implicated FtsI; in this case, the substitutions were V511A and R517H. To verify S357N substitution, the protein sequence of H. influenzae FtsI was threaded through the S. pneumoniae PBP 2X structure giving an average root mean square deviation of the 
-carbon chains of 0.5 Å. The S357N substitution alters both the residue size and charge. One explanation for the contribution of S357N to CXMR is that the asparagine side-chain produces unfavourable steric hindrance with the side chain of Val-362 changing the torsion angles of the asparagine residue, which in turn may influence the position of the loop V362–P366 adjacent to the active site. Whilst other groups have examined the contribution of H. influenzae PBPs in ampicillin resistance, this is the first report analysing their role in CXMR.
Keywords: penicillin binding proteins, ß-lactam resistance
* Corresponding author: Tel: +44-117-928-7897; Fax: +44-117-928-7896; E-mail: T.R.Walsh{at}bristol.ac.uk
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