PE/PPE proteins mediate nutrient transport across the outer membrane of <i>Mycobacterium tuberculosis</i>.

Abstract

<i>Mycobacterium tuberculosis</i> has an unusual outer membrane that lacks canonical porin proteins for the transport of small solutes to the periplasm. We discovered that 3,3-<i>bis</i>-di(methylsulfonyl)propionamide (3bMP1) inhibits the growth of <i>M. tuberculosis</i>, and resistance to this compound is conferred by mutation within a member of the proline-proline-glutamate (PPE) family, PPE51. Deletion of PPE51 rendered <i>M. tuberculosis</i> cells unable to replicate on propionamide, glucose, or glycerol. Growth was restored upon loss of the mycobacterial cell wall component phthiocerol dimycocerosate. Mutants in other proline-glutamate (PE)/PPE clusters, responsive to magnesium and phosphate, also showed a phthiocerol dimycocerosate-dependent growth compromise upon limitation of the corresponding substrate. Phthiocerol dimycocerosate determined the low permeability of the mycobacterial outer membrane, and the PE/PPE proteins apparently act as solute-specific channels.