Antibiotic resistance: combining microscopy, microfluidics and genomics to target bacterial DNA repair pathways

Summary

Antibiotic resistance is one of the major health problems of our time. Recent studies indicate, however, that some antibiotic-resistant bacteria have an Achilles heel: they rely on DNA repair processes in order to survive antibiotic treatment. It was found that inactivation of a single DNA repair gene, recA, renders cells carrying fluoroquinolone resistance determinants sensitive to clinically accessible concentrations of ciprofloxacin. Coincident with this discovery, a small-molecule inhibitor has been identified that inhibits RecA activities in vitro and in vivo. There is an immediate opportunity to capitalize on these discoveries. Our team has a unique skill set that will allow us to do just that.

We will combine our expertise in single-molecule microscopy, genetics, microfluidic design and genome analysis to characterise DNA repair in antibiotic- resistant E. coli cells, pinpointing vulnerabilities to be explored in future drug discovery efforts. In complementary work, we will develop new microfluidic tools for experimental evolution that will allow us to experimentally test models for the evolution of fluoroquinolone resistance and identify if there are readily available routes towards resistance against DNA repair inhibitors.

This study will pave the way for DNA repair as a novel drug target. It will also help us to pre-emptively identify evolutionary routes that could lead to resistance against repair inhibitors. The microfluidic devices we develop will have application beyond the immediate project: they will serve as much-needed experimental evolution platforms for testing how likely bacteria are to develop resistance to new drugs, and to simulate the long-term resistance outcomes of different therapeutic strategies. Importantly, the single-cell devices we develop could be readily adapted for use in rapid diagnostic testing.