Structure-Resistance Relationships: Interrogating Antiseptic Resistance in Bacteria with Multicationic Quaternary Ammonium Dyes
Structure-Resistance Relationships: Interrogating Antiseptic Resistance in Bacteria with Multicationic Quaternary Ammonium Dyes
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DOI：
10.1002/cmdc.201600095
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发表时间：
2016-05-06
期刊：
影响因子：
3.4
通讯作者：
Wuest, William M.
中科院分区：
文献类型：
--
作者：
Forman, Megan E.;Fletcher, Madison H.;Wuest, William M.
细菌对常用杀生物剂的耐药性是一个普遍但未被充分认识的问题，不仅需要更深入地了解耐药性扩散的机制，而且还需要缓解的手段。为了推进我们对这个问题的理解，我们认识到一个多环芳烃结构的核心类似于激活剂的QacR，负转录调节剂的外排泵QacA，并设想了一系列的季铵化合物（QACs）基于这个主题。使用市售的染料支架，我们合成并评价了52种具有1-3个季铵中心的新型QAC的抗菌活性。已经观察到针对携带QAC抗性基因的细菌的抗微生物活性的显著差异，针对已知携带外排泵的细菌的选择结构的最小抑制浓度（MIC）增加高达125倍。基于这些研究结果，结构阻力关系的一般趋势已经确定，奠定了基础，为今后的机制研究。
Bacterial resistance toward commonly used biocides is a widespread yet underappreciated problem, one which needs not only a deeper understanding of the mechanisms by which resistance proliferates, but also means for mitigation. To advance our understanding of this issue, we recognized a polyaromatic structural core analogous to activators of QacR, a negative transcriptional regulator of the efflux pump QacA, and envisioned a series of quaternary ammonium compounds (QACs) based on this motif. Using commercially available dye scaffolds, we synthesized and evaluated the antimicrobial activity of 52 novel QACs bearing 1-3 quaternary ammonium centers. Striking differences in antimicrobial activity against bacteria bearing QAC resistance genes have been observed, with up to a 125-fold increase in minimum inhibitory concentration (MIC) for select structures against bacteria known to bear efflux pumps. Based on these findings, general trends in structure-resistance relationships have been identified, laying the groundwork for future mechanistic studies.