PE/PPE proteins contribute todrug resistance.

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() drug transport and resistance. Mutations in multiplegenes were strongly associated with drug resistance in a genetic association study, and mutations inandalso conferred increased resistance. Deletion of apair transcriptionally responsive to drug exposure,, led to elevated resistance to isoniazid (INH) across all majorlineages and accelerated INH resistance emergence. These data identify a role forPE/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 ofclinical drug resistance.