The Gram-negative permeability barrier: tipping the balance of the in and the out

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.

Keywords: Gram-negative bacteria; antibiotic resistance; cell envelope.

Fig 1

Simplified depictions of the cell envelopes of Gram-positive (A) and Gram-negative (B) bacteria. Both envelope types contain a cytoplasmic membrane (often termed the inner membrane in Gram-negatives) consisting of phospholipids, surrounded by a peptidoglycan layer. In Gram-positives, the peptidoglycan layer is thicker and contains teichoic acids bound to the peptidoglycan only (wall teichoic acids) or peptidoglycan and the cell membrane (lipoteichoic acids). Gram-negative species possess a second, outer membrane that has an inner leaflet composed mainly of phospholipids and an outer leaflet composed mainly of lipopolysaccharides (LPS). The LPS molecules (C) consist of three components: lipid A, a variable oligosaccharide core, and a variable oligosaccharide chain termed O-antigen. As well as lipids, both membranes also contain proteins. The cytoplasmic membrane contains uptake proteins and efflux pumps, which in Gram-negatives can be either single component pumps spanning the inner membrane or tripartite pumps spanning both membranes. The outer membrane of Gram-negatives also contains specific uptake channels and general porins.