Abstract
The outer membrane (OM) of mycobacteria is a formidable permeability barrier that confers drug tolerance, and whether drugs traverse the OM by mechanisms beyond passive diffusion remains unclear. The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) proteins of pathogenic mycobacteria include several OM transporters. Here, we tested the role of PE/PPE proteins in Mycobacterium tuberculosis ( Mtb ) drug transport and resistance. Mutations in multiple pe/ppe genes were strongly associated with drug resistance in a genetic association study, and mutations in ppe42 and ppe51 also conferred increased resistance in vitro . Deletion of a pe/ppe pair transcriptionally responsive to drug exposure, pe25/ppe41 , led to elevated resistance to isoniazid (INH) across all major Mtb lineages and accelerated INH resistance emergence in vitro . These data identify a role for Mtb PE/PPE proteins in drug resistance consistent with the PE/PPE transporter paradigm, suggest a broader contribution of this large protein family, and a new factor of Mtb clinical drug resistance.