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bioRxiv · 10.1101/2025.09.24.678375

PE/PPE proteins contribute to Mycobacterium tuberculosis drug resistance

Boradia, V.·Chen, J.·Frando, A.·Clark, L. V.·Grundner, C.
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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.

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Boradia, V., Chen, J., Frando, A., Clark, L. V., Grundner, C.. 2025-09-24. PE/PPE proteins contribute to Mycobacterium tuberculosis drug resistance. https://doi.org/10.1101/2025.09.24.678375

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