JAC Advance Access published online on October 31, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl442
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1 Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
* To whom correspondence should be addressed. Objectives: Disease caused by penicillin-resistant Streptococcus pneumoniae (PRSP) is associated with more suppurative complications than disease caused by penicillin-susceptible S. pneumoniae (PSSP). Exposure of S. pneumoniae to Methods: Both organisms were treated with penicillin or cefotaxime at and around the MIC. TLR2 signalling was measured as relative IL-8 promoter activation in transfected HeLa cells. Results: On exposure to penicillin, log-phase PSSP and PRSP induced TLR2-proinflammatory activation at levels significantly higher than unexposed bacteria, and maximal in each case at the MIC. Transformants containing low-affinity penicillin-binding proteins (PBP) 2x, 1a and 2b exhibited stepwise resistance to cefotaxime and penicillin. TLR2 activation following penicillin treatment was dependent on an abnormal cell wall (PBP1a and 2x) and autolysis (PBP2b). High affinity PBP2x was required for this effect to be observed in log-phase pneumococci exposed to cefotaxime at the MIC. Cefotaxime-mediated TLR2 activation was not observed in lag-phase transformants exposed to sub-lethal concentrations. Conclusions: These data show that PRSP have similar TLR2-proinflammatory effects to PSSP when exposed to
Received July 3, 2006
Revised September 25, 2006
Accepted October 4, 2006
Original article
Proinflammatory activation of Toll-like receptor-2 during exposure of penicillin-resistant Streptococcus pneumoniae to
Lisa J. Moore 1, Andrea M. Gilbey 2 
-lactam antibiotics
, Christopher G. Dowson 2, Alison C. Pridmore 1, Steven K. Dower 1, and Robert C. Read 1 *
2 Department of Biological Sciences, University of Warwick, Coventry, UK
Robert C. Read, E-mail: r.c.read{at}shef.ac.uk
Abstract 
-lactam antibiotics enhances the proinflammatory activation of human cells by pneumococci via Toll-like receptor-2 (TLR2). To test the hypothesis that penicillin resistance influences cellular TLR2 activation by -lactam-exposed pneumococci, we compared TLR2 induction by PSSP (MIC 0.06 mg/L) and a high-level PRSP clinical isolate (159; MIC 16 mg/L) following exposure to penicillin and cefotaxime.-lactam antibiotics but the antibiotic concentration relative to the MIC is critical. This has implications for treatment of pneumococcal disease when tissue concentrations of antibiotic are close to the MIC.Present address. Micropathology Ltd, University of Warwick Science Park, Barclays Venture Centre, Sir William Lyons Road, Coventry CV4 7EZ, UK
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