A voltage-gated porin PPE1 regulates secretion and drug resistance in Mycobacterium tuberculosis
5 affiliations
- 1Immunometabolism Laboratory, BRIC-National Institute of Immunology, New Delhi 110067, India
- 2Membrane Biology Laboratory, Transdisciplinary Research Division, BRIC-Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, India
- 3Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, Karnataka, India
- 4Bioinformatics Centre, Biotechnology Research and Innovation Council-National Institute of Immunology, New Delhi 110067, India
- 5Department of Biology, Indian Institute of Science Education and Research, Pashan, Pune 411008, India
Abstract
Drug resistance in Mycobacterium tuberculosis (Mtb) remains a formidable clinical hurdle, compounded by the fact that the pathways by which antibiotics penetrate its multilayered cell envelope remain incompletely mapped. We identify PPE1 as a voltage-gated outer-membrane porin that mediates the secretion of kupyaphores while also facilitating the uptake of the frontline anti-tubercular drug isoniazid (INH). Genome-wide association analysis of 38,038 clinical isolates links ppe1 mutations with INH resistance, highlighting its clinical relevance. Consistent with this, the Mtb Δppe1 mutant shows increased tolerance to INH, accompanied by markedly reduced intracellular accumulation of INH compared with the wild-type strain. The Δppe1 strain exhibits attenuated infection, impaired growth, and reduced virulence in a murine infection model. Electron microscopy, molecular modeling, and single-channel electrophysiology reveal that PPE1 assembles into an unusual pentameric α-helical channel, distinct from classical β-barrel bacterial porins. Together, our findings identify PPE1 as a key determinant of mycobacterial membrane permeability that coordinates metallophore secretion and also antibiotic influx. This work uncovers a previously unrecognized mechanism governing Mtb physiology, virulence, and drug susceptibility, providing a potential target for therapeutic intervention.
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BibTeX
@article{yadav2026voltagegated,
title = {{A voltage-gated porin PPE1 regulates secretion and drug resistance in Mycobacterium tuberculosis}},
author = {Mohit Yadav and Neilah Firzan C. A. and Dipanwita Mandal and Jyotsna Shukla and Binayak Sarkar and Sanjeet Kumar Mahtha and Aakash Chandramouli and Abhishek Prasad and Siddhesh S. Kamat and Debasisa Mohanty and Somnath Dutta and Kozhinjampara R. Mahendran and Rajesh S. Gokhale},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2602335123},
url = {https://doi.org/10.1073/pnas.2602335123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A voltage-gated porin PPE1 regulates secretion and drug resistance in Mycobacterium tuberculosis
AU - Mohit Yadav
AU - Neilah Firzan C. A.
AU - Dipanwita Mandal
AU - Jyotsna Shukla
AU - Binayak Sarkar
AU - Sanjeet Kumar Mahtha
AU - Aakash Chandramouli
AU - Abhishek Prasad
AU - Siddhesh S. Kamat
AU - Debasisa Mohanty
AU - Somnath Dutta
AU - Kozhinjampara R. Mahendran
AU - Rajesh S. Gokhale
PY - 2026
DA - 2026/10/27
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2602335123
UR - https://doi.org/10.1073/pnas.2602335123
AB - Drug resistance in Mycobacterium tuberculosis (Mtb) remains a formidable clinical hurdle, compounded by the fact that the pathways by which antibiotics penetrate its multilayered cell envelope remain incompletely mapped. We identify PPE1 as a voltage-gated outer-membrane porin that mediates the secretion of kupyaphores while also facilitating the uptake of the frontline anti-tubercular drug isoniazid (INH). Genome-wide association analysis of 38,038 clinical isolates links ppe1 mutations with INH resistance, highlighting its clinical relevance. Consistent with this, the Mtb Δppe1 mutant shows increased tolerance to INH, accompanied by markedly reduced intracellular accumulation of INH compared with the wild-type strain. The Δppe1 strain exhibits attenuated infection, impaired growth, and reduced virulence in a murine infection model. Electron microscopy, molecular modeling, and single-channel electrophysiology reveal that PPE1 assembles into an unusual pentameric α-helical channel, distinct from classical β-barrel bacterial porins. Together, our findings identify PPE1 as a key determinant of mycobacterial membrane permeability that coordinates metallophore secretion and also antibiotic influx. This work uncovers a previously unrecognized mechanism governing Mtb physiology, virulence, and drug susceptibility, providing a potential target for therapeutic intervention.
SN - 0027-8424
SN - 1091-6490
ER -