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

Abstract

2The mycomembrane layer of the mycobacterial cell envelope is a barrier to 3 environmental, immune and antibiotic insults. We find that there is mycomembrane 4 remodeling along the periphery of nutrient-starved, non-replicating mycobacterial cells. 5Remodeling is supported by recycling of trehalose, a non-mammalian disaccharide that 6 shuttles long-chain mycolate lipids to the mycomembrane. In the absence of trehalose 7 recycling, mycomembrane synthesis continues but mycobacteria experience ATP 8 depletion, enhanced respiration and redox stress. Redox stress from depletion of the 9 trehalose pool is suppressed in a mutant that lacks the OtsAB de novo trehalose 10 synthesis pathway. Our data suggest that trehalose recycling alleviates the energetic 11 burden of mycomembrane remodeling. Loss of trehalose salvage is known to attenuate 12

The role of chemoenzymatic synthesis in advancing trehalose analogues as tools for combatting bacterial pathogens

“…LpqY-SugABC recycles free trehalose released via Ag85 mycoloyltransferase activity, and it can also mediate uptake of exogenous trehalose from the environment. 59,60 Collectively, this remarkable network of trehalose metabolic pathways is extremely important to mycobacteria, with many steps being essential for viability (e.g., trehalose biosynthesis, MmpL3, Ag85), and other steps contributing to mycobacterial stress adaptation and/or virulence (e.g., LpqY-SugABC, TreS, Tdmh). Thus, there has been significant effort to investigate these mycobacterial pathways and target them for diagnostic and therapeutic applications, as discussed extensively in this article.…”

Versatile approach towards fully desymmetrized trehalose with a novel set of orthogonal protecting groups

“…Given the continuous progress in the study of trehalosedependent mycobacterial biology and the discovery of new trehalose-recognizing proteins (such as the LpqY-SugABC transporter) (Parker et al, 2020;Furze et al, 2021;Pohane et al, 2021), as well as the ongoing efforts to develop novel Mincledependent vaccine adjuvants, a practical, easily reproducible and scalable approach to the synthesis of multipurpose desymmetrized trehalose scaffolds is in great demand. With this in mind, we aimed to develop a straightforward and efficient multi-gram-scale synthetic approach towards fully desymmetrized orthogonally protected trehaloses, which can then be used as versatile building blocks in the assembly of complex trehalose-based glycans, or as scaffolds for the introduction of reporter groups for biorthogonal chemistry and the study of trehalose pathways in mycobacteria.…”