Our
limited understanding of the molecular basis for compound entry into and efflux
out of Gram-negative bacteria is now recognized as a key bottleneck for the
rational discovery of novel antibacterial compounds. Traditional, large-scale
biochemical or target-agnostic phenotypic antibacterial screening efforts have,
as a result, not been very fruitful. A main driver of this knowledge gap has
been the historical lack of predictive cellular assays, tools, and models that
provide structure–activity relationships to inform optimization of compound
accumulation. A variety of recent approaches has recently been described to
address this conundrum. This Perspective explores these approaches and
considers ways in which their integration could successfully redirect
antibacterial drug discovery efforts.
Posted by Dr. Tim Sandle,
Pharmaceutical Microbiology