Abstract
Gram-negative bacteria are intrinsically resistant to many antibiotics, due in large part to the permeability barrier formed by their cell envelope. The complex and synergistic interplay of the two Gram-negative membranes and active efflux prevents the accumulation of a diverse range of compounds that are effective against Gram-positive bacteria. A lack of detailed information on how components of the cell envelope contribute to this has been identified as a key barrier to the rational development of new antibiotics with efficacy against Gram-negative species. This review describes the current understanding of the role of the different components of the Gram-negative cell envelope in preventing compound accumulation and the state of efforts to describe properties that allow compounds to overcome this barrier and apply them to the development of new broad-spectrum antibiotics.