Trehalose recycling promotes energy-efficient mycomembrane reorganization in nutrient-limited mycobacteria

The mycomembrane layer of the mycobacterial cell envelope is a barrier to environmental, immune and antibiotic insults. We find that there is mycomembrane remodeling along the periphery of nutrient-starved, non-replicating mycobacterial cells. Remodeling is supported by recycling of trehalose, a non-mammalian disaccharide that shuttles long-chain mycolate lipids to the mycomembrane. In the absence of trehalose recycling, mycomembrane synthesis continues but mycobacteria experience ATP depletion, enhanced respiration and redox stress. Redox stress from depletion of the trehalose pool is suppressed in a mutant that lacks the OtsAB de novo trehalose synthesis pathway. Our data suggest that trehalose recycling alleviates the energetic burden of mycomembrane remodeling. Loss of trehalose salvage is known to attenuate M. tuberculosis during infection and render the bacterium more susceptible to a variety of drugs. Recycling pathways are emerging targets for sensitizing resource-limited bacterial pathogens to host and antibiotic stress.