Mastering the Gram-negative bacterial barrier – Chemical approaches to increase bacterial bioavailability of antibiotics

[Display omitted] To win the battle against resistant, pathogenic bacteria, novel classes of anti-infectives and targets are urgently needed. Bacterial uptake, distribution, metabolic and efflux pathways of antibiotics in Gram-negative bacteria determine what we here refer to as bacterial bioavailability. Understanding these mechanisms from a chemical perspective is essential for anti-infective activity and hence, drug discovery as well as drug delivery. A systematic and critical discussion of in bacterio, in vitro and in silico assays reveals that a sufficiently accurate holistic approach is still missing. We expect new findings based on Gram-negative bacterial bioavailability to guide future anti-infective research.