Inactivation of tesA reduces cell wall lipid production and increases drug susceptibility in mycobacteria

Sivagami Sundaram Chavadi, Uthamaphani R. Edupuganti, Olivia M. Vergnolle, Itrat Fatima, Shaneen M. Singh, Clifford E. Soll, Luis E N Quadri

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs) are structurally related lipids noncovalently bound to the outer cell wall layer of Mycobacterium tuberculosis, Mycobacterium leprae, and several opportunistic mycobacterial human pathogens. PDIMs and PGLs are important effectors of virulence. Elucidation of the biosynthesis of these complex lipids will not only expand our understanding of mycobacterial cell wall biosynthesis, but it may also illuminate potential routes to novel therapeutics against mycobacterial infections. We report the construction of an in-frame deletion mutant of tesA (encoding a type II thioesterase) in the opportunistic human pathogen Mycobacterium marinum and the characterization of this mutant and its corresponding complemented strain control in terms of PDIM and PGL production. The growth and antibiotic susceptibility of these strains were also probed and compared with the parental wild-type strain.Weshow that deletion of tesA leads to a mutant that produces only traces of PDIMs and PGLs, has a slight growth yield increase and displays a substantial hypersusceptibility to several antibiotics. We also provide a robust model for the three-dimensional structure of M. marinum TesA (TesAmm) and demonstrate that a Ser-to-Ala substitution in the predicted catalytic Ser of TesAmm renders a mutant that recapitulates the phenotype of the tesA deletion mutant. Overall, our studies demonstrate a critical role for tesA in mycobacterial biology, advance our understanding of the biosynthesis of an important group of polyketide synthase-derived mycobacterial lipids, and suggest that drugs aimed at blocking PDIM and/or PGL production might synergize with antibiotic therapy in the control of mycobacterial infections.

Original languageEnglish (US)
Pages (from-to)24616-24625
Number of pages10
JournalJournal of Biological Chemistry
Volume286
Issue number28
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

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Glycolipids
Mycobacterium
Cell Wall
Cells
Biosynthesis
Lipids
Mycobacterium marinum
Pharmaceutical Preparations
Pathogens
Anti-Bacterial Agents
Strain control
Polyketide Synthases
Mycobacterium leprae
Infection Control
Growth
Mycobacterium tuberculosis
Virulence
Substitution reactions
phthiocerol dimycocerosate
Phenotype

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Inactivation of tesA reduces cell wall lipid production and increases drug susceptibility in mycobacteria. / Chavadi, Sivagami Sundaram; Edupuganti, Uthamaphani R.; Vergnolle, Olivia M.; Fatima, Itrat; Singh, Shaneen M.; Soll, Clifford E.; Quadri, Luis E N.

In: Journal of Biological Chemistry, Vol. 286, No. 28, 15.07.2011, p. 24616-24625.

Research output: Contribution to journalArticle

Chavadi, Sivagami Sundaram ; Edupuganti, Uthamaphani R. ; Vergnolle, Olivia M. ; Fatima, Itrat ; Singh, Shaneen M. ; Soll, Clifford E. ; Quadri, Luis E N. / Inactivation of tesA reduces cell wall lipid production and increases drug susceptibility in mycobacteria. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 28. pp. 24616-24625.
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AU - Fatima, Itrat

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AU - Soll, Clifford E.

AU - Quadri, Luis E N

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