Effect of phenolic glycolipids from Mycobacterium kansasii on proinflammatory cytokine release. A structure-activity relationship study.

The cell wall of pathogenic mycobacteria is abundant with virulence factors, among which phenolic glycolipids (PGLs) are prominent examples. Mycobacterium kansasii, an important opportunistic pathogen, produces seven PGLs and their effect on the release of important proinflammatory cytokines that mediate disease progression has not been investigated. We previously showed that proinflammatory cytokines are modulated by PGLs from M. tuberculosis, M. leprae and M. bovis. In this paper we describe the synthesis of a series of 17 analogs of M. kansasii PGLs containing a truncated aglycone. Subsequently, the effect of these compounds on the release of proinflammatory cytokines (TNF-α, IL-6, IL-1ß, MCP-1) and nitric oxide (NO) was evaluated. These compounds exerted an immunoinhibitory effect on the release of the tested cytokines. The concentration-dependent inhibitory profile of the tested molecules was also found to be dependent on the methylation pattern of the molecule and was mediated via toll-like receptor (TLR)-2. This study led to the discovery of a glycolipid (18) that shows promising potent anti-inflammatory properties making it a potential candidate for further optimization of its anti-inflammatory profile.

Mycobacterial phenolic glycolipids with a simplified lipid aglycone modulate cytokine levels through Toll-like receptor 2.

Phenolic glycolipids (PGLs) are virulence factors present in the cell walls of many pathogenic mycobacteria. PGLs have been implicated in various aspects of mycobacterial disease, but there are limited structure-activity data available for these molecules. We report here the preparation of seven synthetic PGL analogues, differing from the native compounds in the replacement of the complex phenolic lipid moiety with a p-methoxyphenyl group. The ability of these compounds to stimulate or inhibit the production of cytokines (TNF-α, IL-1ß, IL-6, MCP-1) and nitric oxide (NO) was then evaluated by ELISA-based assays. None of the compounds stimulated the production of these biological signalling molecules. In contrast, they each displayed concentration-dependent inhibitory activity, related to the methylation pattern of the molecule and mediated by Toll-like receptor 2. Additional studies revealed that native PGL-I from Mycobacterium leprae and a synthetic PGL-I analogue containing a simplified lipid domain had enhanced inhibitory activities relative to the corresponding analogues containing the p-methoxyphenyl aglycone; however, the natural lipid phenolthiocerol was only weakly active. These studies reveal that synthetic molecules of this type can be used as probes for PGL function. Moreover, their ease of synthesis relative to the natural glycolipids, as well as their more favourable aqueous solubility, should allow for more thorough structure-activity relationship studies.