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The Mycobacterium tuberculosis Virulence Factor Trehalose Dimycolate Imparts Desiccation Resistance to Model Mycobacterial Membranes

Christopher W. Harland ^*, David Rabuka , Carolyn R. Bertozzi    ^¶ and Raghuveer Parthasarathy ^*

^* Department of Physics and Materials Science Institute, University of Oregon, Eugene, Oregon 94703; Department of Chemistry, University of California, Berkeley, California 94720; Department of Molecular and Cell Biology, University of California, Berkeley, California 94720; Physical Bioscience and Materials Science Divisions, Lawrence Berkeley National Laboratory, Berkeley, California 94720; and ^¶ Howard Hughes Medical Institute, University of California, Berkeley, California 94720

Correspondence: Address reprint requests to Raghuveer Parthasarathy, E-mail: raghu{at}uoregon.edu.

Mycobacteria, including persistent pathogens like Mycobacterium tuberculosis, have an unusual membrane structure in which, outside the plasma membrane, a nonfluid hydrophobic fatty acid layer supports a fluid monolayer rich in glycolipids such as trehalose 6,6'-dimycolate (TDM; cord factor). Given the abilities of mycobacteria to survive desiccation and trehalose in solution to protect biomolecules and whole organisms during freezing, drying, and other stresses, we hypothesized that TDM alone may suffice to confer dehydration resistance to the membranes of which it is a constituent. We devised an experimental model that mimics the structure of mycobacterial envelopes in which an immobile hydrophobic layer supports a TDM-rich, two-dimensionally fluid leaflet. We have found that TDM monolayers, in stark contrast to phospholipid membranes, can be dehydrated and rehydrated without loss of integrity, as assessed by fluidity and protein binding. Strikingly, this protection from dehydration extends to TDM-phospholipid mixtures with as little as 25 mol % TDM. The dependence of the recovery of membrane mobility upon rehydration on TDM fraction shows a functional form indicative of spatial percolation, implying that the connectivity of TDM plays a crucial role in membrane preservation. Our observations are the first reported instance of dehydration resistance provided by a membrane glycolipid.