Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom.
Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom
Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17011-17018. doi: 10.1073/pnas.2003271117. Epub 2020 Jul 7.
Few antibiotics are effective against , one of the most successful pathogens responsible for hospital-acquired infections. Resistance to chlorhexidine, an antiseptic widely used to combat , is effected through the proteobacterial antimicrobial compound efflux (PACE) family. The prototype membrane protein of this family, AceI ( chlorhexidine efflux protein I), is encoded for by the gene and is under the transcriptional control of AceR ( chlorhexidine efflux protein regulator), a LysR-type transcriptional regulator (LTTR) protein. Here we use native mass spectrometry to probe the response of AceI and AceR to chlorhexidine assault. Specifically, we show that AceI forms dimers at high pH, and that binding to chlorhexidine facilitates the functional form of the protein. Changes in the oligomerization of AceR to enable interaction between RNA polymerase and promoter DNA were also observed following chlorhexidine assault. Taken together, these results provide insight into the assembly of PACE family transporters and their regulation via LTTR proteins on drug recognition and suggest potential routes for intervention.
针对 ，很少有抗生素是有效的，它是导致医院获得性感染的最成功病原体之一。 对氯己定的耐药性，氯己定是一种广泛用于对抗的防腐剂，是通过细菌抗菌化合物外排（PACE）家族实现的。该家族的原型膜蛋白 AceI（氯己定外排蛋白 I）由 基因编码，受 AceR（氯己定外排蛋白调节剂）的转录调控，AceR 是一种 LysR 型转录调节蛋白（LTTR）。在这里，我们使用天然质谱法来探测 AceI 和 AceR 对氯己定攻击的反应。具体来说，我们表明 AceI 在高 pH 值下形成二聚体，并且与氯己定结合促进了蛋白质的功能形式。在氯己定攻击后，还观察到 AceR 的寡聚化变化，从而能够在 RNA 聚合酶和启动子 DNA 之间进行相互作用。总之，这些结果深入了解了 PACE 家族转运蛋白的组装及其通过 LTTR 蛋白在药物识别中的调节，并为潜在的干预途径提供了依据。
