The bacterial outer membrane is an evolving antibiotic barrier

The outer membrane (OM) of the diderm “gram-negative” class of bacteria is an essential organelle and a robust permeability barrier that prevents many antibiotics from reaching their intracellular targets (1). The OM is a unique asymmetrical lipid bilayer (Fig. 1): The inner leaflet is composed of phospholipids (PLs), and the outer leaflet consists almost exclusively of a glycolipid referred to either as lipopolysaccharide (LPS, in bacteria that attach long repeats of sugars to the glycolipid) or lipooligosaccharide (LOS, in bacteria that attach only a short oligosaccharide to cap the glycolipid) (1). Assembly of these lipids into a contiguous barrier, and how that barrier is maintained in response to damage, is a fascinating biological problem. Both PLs and LPS/LOS are synthesized inside the cell, so they must first transit the inner membrane (IM) and then traverse the hostile aqueous periplasmic environment before being assembled into an OM. Work over the past decade uncovered a protein bridge that links the IM and OM and allows LPS/LOS to flow directly into the OM outer leaflet (2). How PLs are transported to the OM remains a mystery. Understanding the pathways of OM biogenesis is a pressing goal. New antibiotics against gram-negative bacteria are urgently needed (3). Rates of antibiotic resistance continue to rise unabated, while the last truly novel antibiotic effective against gram-negative bacteria was discovered in the 1960s (3). The hope is that treatments interfering with OM biogenesis will offer new lethal therapeutics or will help permeabilize gram-negative bacteria to existing drugs. Until that promise is realized, clinicians are increasingly forced to rely on last-resort antibiotics that were once sidelined due to their unfavorable toxicity profiles, including the OM-targeting antibiotic colistin (polymyxin E) (4). In PNAS, Powers and Trent (5) provide new insights into how colistin-resistant bacteria evolve improved fitness by altering their …

↵¹To whom correspondence should be addressed. Email: marcin.grabowicz{at}emory.edu.