Fluorescent macrolide probes – synthesis and use in evaluation of bacterial resistance,RSC Chemical Biology

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Fluorescent macrolide probes – synthesis and use in evaluation of bacterial resistance
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-11-17 , DOI: 10.1039/d0cb00118j
M Rhia L Stone ₁ , Urszula Łapińska ₂ , Stefano Pagliara ₂ , Muriel Masi ₃ , Joanne T Blanchfield ₄ , Matthew A Cooper ₁ , Mark A T Blaskovich ₁

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The emerging crisis of antibiotic resistance requires a multi-pronged approach in order to avert the onset of a post-antibiotic age. Studies of antibiotic uptake and localisation in live cells may inform the design of improved drugs and help develop a better understanding of bacterial resistance and persistence. To facilitate this research, we have synthesised fluorescent derivatives of the macrolide antibiotic erythromycin. These analogues exhibit a similar spectrum of antibiotic activity to the parent drug and are capable of labelling both Gram-positive and -negative bacteria for microscopy. The probes localise intracellularly, with uptake in Gram-negative bacteria dependent on the level of efflux pump activity. A plate-based assay established to quantify bacterial labelling and localisation demonstrated that the probes were taken up by both susceptible and resistant bacteria. Significant intra-strain and -species differences were observed in these preliminary studies. In order to examine uptake in real-time, the probe was used in single-cell microfluidic microscopy, revealing previously unseen heterogeneity of uptake in populations of susceptible bacteria. These studies illustrate the potential of fluorescent macrolide probes to characterise and explore drug uptake and efflux in bacteria.

中文翻译：

荧光大环内酯探针——合成和用于评价细菌耐药性

新出现的抗生素耐药性危机需要多管齐下的方法，以避免后抗生素时代的到来。活细胞中抗生素摄取和定位的研究可为改进药物的设计提供信息，并有助于更好地了解细菌耐药性和持久性。为了促进这项研究，我们合成了大环内酯类抗生素红霉素的荧光衍生物。这些类似物表现出与母体药物相似的抗生素活性谱，并且能够标记革兰氏阳性和阴性细菌以进行显微镜检查。探针定位于细胞内，革兰氏阴性细菌的摄取取决于外排泵活动的水平。为量化细菌标记和定位而建立的基于平板的测定表明探针被敏感和抗性细菌吸收。在这些初步研究中观察到显着的菌株内和种内差异。为了实时检查摄取情况，该探针用于单细胞微流体显微镜，揭示了以前未见的易感细菌群体摄取的异质性。这些研究说明了荧光大环内酯探针在表征和探索细菌中药物摄取和流出方面的潜力。揭示了以前未见的易感细菌群体摄取的异质性。这些研究说明了荧光大环内酯探针在表征和探索细菌中药物摄取和流出方面的潜力。揭示了以前未见的易感细菌群体摄取的异质性。这些研究说明了荧光大环内酯探针在表征和探索细菌中药物摄取和流出方面的潜力。

更新日期：2020-11-17

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