Bacteria are becoming resistant to every antibiotic, leading to multi-drug resistant ‘superbugs’ that are predicted to kill millions of people each year by 2050. New antibiotics are urgently needed, but few new drugs are available or in clinical development. It is imperative to discover and develop new antibiotics to fight these superbugs, but for this to occur we require an improved understanding of how antibiotics work and how bacteria function and develop resistance. This requires new tools and techniques to advance our knowledge of bacterial metabolism, efflux pumps and other responses to antibiotics, allowing for analysis of key aspects of bacterial growth, division, metabolism and resistance. In order to create such tools, we have been systematically converting representatives of the major classes of antibiotics into mechanism-specific fluorescent probes that retain the biological profile of the parent compound.
This talk will present examples of how these probes are able to provide information about bacterial resistance mechanisms by assessing membrane permeability and efflux pump activity, including preliminary studies using single cell analysis in microfluidic devices. We will also show how the probes can decipher differences in the mechanism of action of antibiotics which possess strikingly different activity against resistant bacteria, despite structural similarity. The probes have also been used to assess potential mechanisms of antibiotic toxicity to human cells. Finally, we will present preliminary studies on extending the application of these probes to whole body imaging, developing diagnostics for clinical use that can specifically identify bacterial infections and distinguish them from inflammation.