Issue 5, 2020

Fluorescent macrolide probes – synthesis and use in evaluation of bacterial resistance

Abstract

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.

Graphical abstract: Fluorescent macrolide probes – synthesis and use in evaluation of bacterial resistance

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Article information

Article type
Paper
Submitted
09 7月 2020
Accepted
28 10月 2020
First published
17 11月 2020
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2020,1, 395-404

Fluorescent macrolide probes – synthesis and use in evaluation of bacterial resistance

M. R. L. Stone, U. Łapińska, S. Pagliara, M. Masi, J. T. Blanchfield, M. A. Cooper and M. A. T. Blaskovich, RSC Chem. Biol., 2020, 1, 395 DOI: 10.1039/D0CB00118J

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