A voltage-gated porin PPE1 regulates secretion and drug resistance in Mycobacterium tuberculosis.

PPE1, a voltage-gated outer-membrane porin in Mycobacterium tuberculosis, is linked to isoniazid resistance, with ppe1 mutations in 38,038 clinical isolates.

• Why it matters: Antibiotic penetration through the multilayered M. tuberculosis cell envelope is incompletely mapped, limiting understanding of how resistance emerges and how permeability is controlled.
• What they did: Genome-wide association analysis of 38,038 clinical isolates was combined with phenotyping of the M. tuberculosis Δppe1 mutant, including INH accumulation measurements and a murine infection model, plus electron microscopy, molecular modeling, and single-channel electrophysiology.
• The result: The Δppe1 mutant shows increased INH tolerance and markedly reduced intracellular INH accumulation versus wild type, and it has attenuated infection, impaired growth, and reduced virulence in mice, while PPE1 forms an unusual pentameric α-helical channel.