Grant: Project Grant

Rising antibiotic resistance across the world is one of the biggest threats to global heath today. Discovery of new classes of antibiotics stalled in the mid-1980s and the few antibiotics brought to market in the past 30 years have been variations on existing drugs. Of greatest concern is that it was as long ago as 1962 that the last new class of antibiotics to treat those infected by the most resistant Gram-negative superbugs - designated priority pathogens by the World Health Organization - was discovered. Such bacteria pose a significant scientific challenge due to powerful intrinsic defense mechanisms that prevent compounds from accumulating. Indeed, crossing the Gram-negative bacterial membrane poses a major challenge to antibiotic development, as many small molecules that can biochemically inhibit key bacterial processes are rendered ineffective by poor cellular uptake. This proposal seeks to investigate the influence of energetics at the level of the cell membrane in mediating compound accumulation in bacteria. This detailed information is needed to fully understand how to better design antibiotics that exploit these phenomena which are universal and intrinsic to bacterial pathogens.