Moore Lisa J, Gilbey Andrea M, Dowson Christopher G, Pridmore Alison C, Dower Steven K, Read Robert C
Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
J Antimicrob Chemother. 2007 Jan;59(1):35-42. doi: 10.1093/jac/dkl442. Epub 2006 Oct 31.
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 beta-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 beta-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.
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.
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.
These data show that PRSP have similar TLR2-proinflammatory effects to PSSP when exposed to beta-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.
耐青霉素肺炎链球菌（PRSP）引起的疾病比青霉素敏感肺炎链球菌（PSSP）引起的疾病伴有更多化脓性并发症。肺炎链球菌暴露于β-内酰胺类抗生素会通过Toll样受体2（TLR2）增强肺炎链球菌对人细胞的促炎激活作用。为了验证青霉素耐药性会影响β-内酰胺类抗生素暴露的肺炎链球菌对细胞TLR2激活作用这一假说，我们比较了PSSP（MIC 0.06 mg/L）和一株高水平PRSP临床分离株（159；MIC 16 mg/L）在暴露于青霉素和头孢噻肟后的TLR2诱导情况。
两种菌株均在MIC及MIC附近用青霉素或头孢噻肟处理。通过转染HeLa细胞中相对IL-8启动子激活来测量TLR2信号传导。
暴露于青霉素后，对数期PSSP和PRSP诱导的TLR2促炎激活水平显著高于未暴露的细菌，且每种情况下在MIC时达到最大值。含有低亲和力青霉素结合蛋白（PBP）2x、1a和2b的转化体对头孢噻肟和青霉素表现出逐步耐药性。青霉素处理后的TLR2激活取决于异常细胞壁（PBP1a和2x）和自溶（PBP2b）。在MIC时暴露于头孢噻肟的对数期肺炎链球菌中观察到这种效应需要高亲和力PBP2x。在暴露于亚致死浓度的迟滞期转化体中未观察到头孢噻肟介导的TLR2激活。
这些数据表明，PRSP在暴露于β-内酰胺类抗生素时对TLR2具有与PSSP相似的促炎作用，但相对于MIC的抗生素浓度至关重要。这对于抗生素组织浓度接近MIC时肺炎球菌疾病的治疗具有重要意义。
