Grant: Project Grant

Bacterial infections are a leading cause of hospitalization and death worldwide. Antibiotics are central to our ability to treat bacterial infections, but our capacity to cure these infections is jeopardized by increasing antibiotic resistance (where bacteria are no longer killed by an antibiotic). Added to this, very few new antibiotics with activity against resistant bacteria are being discovered. Therefore, it is essential that we preserve the effective use of the antibiotics we have. Antibiotic tolerance is emerging as a precursor to resistance that also contributes to antibiotic treatment failures in its own right. Tolerance occurs when bacteria are still killed by antibiotics, but die slower than usual. This means that live bacteria remain at the end of a typical course of antibiotics, resulting in infections that are persistent and recurrent. Persistent infections are associated with higher healthcare costs and death rates than resolving infections. While antibiotic resistance is routinely screened for in clinical laboratories, there are currently no appropriate tests that can detect tolerance. Therefore, the prevalence and consequences of antibiotic tolerance in terms of treatment failures are unknown and likely under-appreciated. We propose to develop a simple screen to detect tolerance and apply it to libraries of bacterial isolates derived from patients with persistent infections, thereby illuminating the true magnitude of this threat to effective antibiotic therapy. We will also investigate one of the mechanisms behind tolerance with a view to understanding how we can reverse it and preserve the effectiveness of existing antibiotics. Our research will improve the treatment of persistent infections by providing physicians with a tool to detect tolerance, as well as practical information on which types of antibiotic are most effective against tolerant bacteria. By targeting antibiotic tolerance, we aim to tackle it before it develops into resistance.