Both Phthiocerol Dimycocerosates and Phenolic Glycolipids Are Required for Virulence of Mycobacterium marinum

Abstract

ABSTRACTPhthiocerol dimycocerosates (PDIMs) and structurally related phenolic glycolipids (PGLs) are complex cell wall lipids unique to pathogenic mycobacteria. While these lipids have been extensively studied in recent years, there are conflicting reports on some aspects of their biosynthesis and on the role of PDIMs and especially PGLs in virulence ofMycobacterium tuberculosis. This has been complicated by the natural deficiency of PGLs in many clinical strains ofM. tuberculosisand the frequent loss of PDIMs in laboratoryM. tuberculosisstrains. In this study, we isolated seven mutants ofMycobacterium marinumdeficient in PDIMs and/or PGLs in which multiple genes of the PDIM/PGL biosynthetic locus were disrupted by transposon insertion. Zebrafish infection experiments showed thatM. marinumstrains lacking one or both of these lipids were avirulent, suggesting that both PDIMs and PGLs are required for virulence. We also found that these strains were hypersensitive to antibiotics and exhibited increased cell wall permeability. Our studies provide new insights into the biosynthesis of PDIMs/PGLs and may help us to understand the role of PDIMs and PGLs inM. tuberculosisvirulence.