Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
J Antimicrob Chemother. 2010 Oct;65(10):2076-82. doi: 10.1093/jac/dkq287. Epub 2010 Aug 13.
Active efflux is a common mechanism of resistance to fluoroquinolones in Streptococcus pneumoniae. Two efflux systems have been described so far in this species: PmrA, a member of the major facilitator superfamily; and the two ABC transporters PatA and PatB. We studied the inducibility of expression of pmrA, patA and patB by using subinhibitory concentrations of fluoroquinolones.
A wild-type susceptible strain, two clinical isolates resistant to fluoroquinolones and two efflux mutants selected in vitro after exposure to ciprofloxacin were studied. MICs were determined for these strains and their mutants in which pmrA, patA or patB had been disrupted. Gene expression was determined after exposure to half the MIC of norfloxacin, ciprofloxacin, levofloxacin, moxifloxacin or gemifloxacin and quantified by real-time PCR.
Increased MICs of norfloxacin, ciprofloxacin and levofloxacin (to a lesser extent) and increased expression of patA and patB were seen for all resistant strains; these were reduced in patA or patB disruptants or in the presence of reserpine. Exposure to any of the five fluoroquinolones caused a reversible increase in expression of patA and patB, but not of pmrA. Mitomycin C, an inducer of the competence system in S. pneumoniae, also induced patA and patB expression in the two strains tested.
The ABC efflux system PatA/PatB is induced upon exposure to subinhibitory concentrations of fluoroquinolones, whether substrates of the transporter or not. This effect, possibly resulting from the activation of the competence pathway, may contribute to resistance.
主动外排是肺炎链球菌对氟喹诺酮类药物耐药的常见机制。迄今为止，在该物种中已经描述了两种外排系统：PmrA，一种主要易化子超家族的成员；和两个 ABC 转运体 PatA 和 PatB。我们研究了亚抑菌浓度的氟喹诺酮类药物对 pmrA、patA 和 patB 表达的诱导作用。
研究了野生敏感株、两株临床分离株对氟喹诺酮类药物的耐药株和体外暴露于环丙沙星后选择的两个外排突变株。测定了这些菌株及其 pmrA、patA 或 patB 缺失突变株的 MIC。用实时 PCR 定量测定了暴露于诺氟沙星、环丙沙星、左氧氟沙星、莫西沙星或加替沙星 MIC 的一半后基因表达情况。
所有耐药株的诺氟沙星、环丙沙星和左氧氟沙星（程度较轻）MIC 增加，patA 和 patB 表达增加；在 patA 或 patB 缺失突变株或加入利血平后，这些增加减少。五种氟喹诺酮类药物中的任何一种都能引起 patA 和 patB 表达的可逆增加，但 pmrA 则不然。丝裂霉素 C，肺炎链球菌感受态系统的诱导剂，也能诱导所测试的两株菌的 patA 和 patB 表达。
无论转运体是否为底物，亚抑菌浓度的氟喹诺酮类药物暴露都会诱导 ABC 外排系统 PatA/PatB 的表达。这种效应可能来自于感受态途径的激活，可能有助于耐药性的产生。
