Decreased outer membrane permeability protects mycobacteria from killing by ubiquitin-derived peptides

Georgiana Purdy, Michael Niederweis, David G. Russell

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Ubiquitin-derived peptides are bactericidal in vitro and contribute to the mycobactericidal activity of the lysosome. To further define interactions of ubiquitinderived peptides with mycobacteria, we screened for mutants with increased resistance to the bactericidal activity of the synthetic ubiquitin-derived peptide Ub2. The four Ub2-resistant Mycobacterium smegmatis mutants were also resistant to the bactericidal action of other antimicrobial peptides and macrophages. Two mutants were in the mspA gene encoding the main M. smegmatis porin. Using a translocation-deficient MspA point mutant, we showed that susceptibility of M. smegmatis to Ub2 was independent of MspA channel activity. Instead, the M. smegmatis Ub2-resistant mutants shared a common phenotype of decreased cell wall permeability compared with wild-type bacteria. Expression of mspA rendered Mycobacterium tuberculosis CDC1551 more susceptible both to ubiquitin-derived peptides in vitro and to lysosomal killing in macrophages. Finally, biochemical assays designed to assess membrane integrity indicated that Ub2 treatment impairs membrane function of M. smegmatis and M. tuberculosis cells. The M. smegmatis Ub2-resistant mutants were more resistant than wild-type M. smegmatis to this damage. We conclude that Ub2 targets mycobacterial membranes and that reduced membrane permeability provides mycobacteria intrinsic resistance against antimicrobial compounds including bactericidal ubiquitin-derived peptides.

Original languageEnglish (US)
Pages (from-to)844-857
Number of pages14
JournalMolecular Microbiology
Volume73
Issue number5
DOIs
StatePublished - Sep 2009

Fingerprint

Mycobacterium smegmatis
Mycobacterium
Ubiquitin
Permeability
Peptides
Membranes
Mycobacterium tuberculosis
Macrophages
Porins
Lysosomes
Cell Wall
Bacteria
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Microbiology

Cite this

Decreased outer membrane permeability protects mycobacteria from killing by ubiquitin-derived peptides. / Purdy, Georgiana; Niederweis, Michael; Russell, David G.

In: Molecular Microbiology, Vol. 73, No. 5, 09.2009, p. 844-857.

Research output: Contribution to journalArticle

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