Mycobacterial Phenolic Glycolipid Virulence Factor Biosynthesis: Mechanism and Small-Molecule Inhibition of Polyketide Chain Initiation

Julian A. Ferreras, Karen L. Stirrett, Xuequan Lu, Jae Sang Ryu, Clifford E. Soll, Derek S. Tan, Luis E E.N. Quadri

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68 Scopus citations

Abstract

Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by Mycobacterium tuberculosis, M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the p-hydroxyphenyl-polyketide moiety of PGLs. Our studies have led to the identification of a stand-alone, didomain initiation module, FadD22, comprised of a p-hydroxybenzoic acid adenylation domain and an aroyl carrier protein domain. FadD22 forms an acyl-S-enzyme covalent intermediate in the p-hydroxyphenyl-polyketide chain assembly line. We also used this information to develop a small-molecule inhibitor of PGL biosynthesis. Overall, these studies provide insights into the biosynthesis of an important group of small-molecule mycobacterial virulence factors and support the feasibility of targeting PGL biosynthesis to develop new drugs to treat mycobacterial infections.

Original languageEnglish
Pages (from-to)51-61
Number of pages11
JournalChemistry and Biology
Volume15
Issue number1
DOIs
StatePublished - 25 Jan 2008

Keywords

  • CHEMBIO
  • MICROBIO

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