Lysins breaking down the walls of Gram-negative bacteria, no longer a no-go.

Phage lysins are one of the most advanced classes of antibacterials under clinical evaluation and have a new mode of action based on peptidoglycan degradation. Lysins were initially excluded from use against Gram-negative pathogens because of their impermeable outer membrane, but are now increasingly developed as effective antibacterials against these critical priority pathogens. Generally, three routes of investigation have been recently explored and advanced to different extents, including the use of lysins that possess intrinsic activity due to a positively charged C-terminus that destabilizes the outer membrane, the use of physical or chemical means to disrupt the outer membrane integrity and protein engineering to equip the lysin with the necessary tools to overcome the outer membrane.