Glycerol Monolaurate Inhibits the Effects of Gram-Positive Select Agents on Eukaryotic Cells

Abstract

Many exotoxins of gram positive bacteria, such as superantigens (staphylococcal enterotoxins, toxic shock syndrome toxin-1 [TSST-1], and streptococcal pyrogenic exotoxins) and anthrax toxin are bioterrorism agents that cause diseases by immunostimulation or cytotoxicity. Glycerol monolaurate (GML), a fatty acid monoester found naturally in humans, has been reported to prevent synthesis of gram positive bacterial exotoxins. This study explored the ability of GML to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from TSS. GML (≥10 ug/ml) inhibited superantigen (5 ug/ml) immunoproliferation, as determined by inhibition of 3 H-thymidine incorporation into DNA of human peripheral blood mononuclear cells (1 × 10 6 cells/ml) as well as phospholipase Cγ1, suggesting inhibition of signal transduction. The compound (20 ug/ml) prevented superantigen (100 ug/ml) induced cytokine secretion by human vaginal epithelial cells (HVECs) as measured by ELISA. GML (250 ug) inhibited rabbit lethality due to TSST-1 administered vaginally. GML (10 ug/ml) inhibited HVEC and macrophage cytotoxicity by anthrax toxin, prevented erythrocyte lysis by purified hemolysins (staphylococcal α and β) and culture fluids containing streptococcal and Bacillus anthracis hemolysins, and was non-toxic to mammalian cells (up to 100 ug/ml) and rabbits (250 ug). GML stabilized mammalian cell membranes, as erythrocyte lysis was reduced in the presence of hypotonic aqueous solutions (0 to 0.05 M saline) or staphylococcal α and β-hemolysins when erythrocytes were pretreated with GML. GML may be useful in management of gram positive exotoxin illnesses; its action appears to be membrane stabilization with inhibition of signal transduction.Many gram positive bacterial pathogens produce exotoxins that are potential agents of bioterrorism and contribute to their abilities to cause human diseases (1-3). Examples include anthrax toxin made by Bacillus anthracis (2), superantigens produced by Staphylococcus aureus, including staphylococcal enterotoxins (SEs) 1 and toxic shock syndrome toxin-1 (TSST-1) (1), and superantigens produced by group A streptococci, including streptococcal pyrogenic exotoxins (SPEs) (3). Other exotoxins, such as staphylococcal α and β-hemolysins and streptolysins, are not agents of bioterrorism but have adjunct roles in virulence and can be used as model toxins to study mechanisms of cellular toxicity.

Glycerol Monolaurate Inhibits Candida and Gardnerella vaginalis In Vitro and In Vivo but Not Lactobacillus

“…However, we recently demonstrated that 5% GML gels, applied vaginally to monkeys, prevented simian immunodeficiency virus (SIV) transmission (16,24) by interference with epithelial cell production of proinflammatory cytokines that attract CD4 T cells into cervical/vaginal tissues. These data agree with prior studies that demonstrate that GML exerts membrane-stabilizing anti-inflammatory effects (21). In our study, GML anti-inflammatory effects are also likely to contribute to interference with VVC and BV.…”

Staphylococcal and Streptococcal Superantigen Exotoxins

“…These studies resulted in additional work that demonstrates that GML inhibits TSST-1 production through interference with bacterial signal transduction (300), reduces S. aureus and group B streptococci vaginally while selecting for the normal flora lactobacilli, and reduces vaginal inflammation as measured by reductions in IL-8 production (301); IL-8 is a chemokine that specifically attracts neutrophils to infection sites. In more recent studies, it has been shown that GML stabilizes and is anti-inflammatory to mucosal epithelial cells as well as other immune cells (302,303). The studies suggest that GML, in addition to preventing TSST-1 production, stabilize the host mucosa to prevent outside-in signaling (109).…”

Surfactants, Aromatic and Isoprenoid Compounds, and Fatty Acid Biosynthesis Inhibitors Suppress Staphylococcus aureus Production of Toxic Shock Syndrome Toxin 1

“…Other investigators have demonstrated that a laurate substituted dodecanoic acid monoester, glycerol monolaurate, retards bacterial virulence factor expression (8,15,20,25,33). An observed problem with glycerol monolaurate was that the ester bond was degraded by human and staphylococcal esterases and lipases, rendering low concentrations of the compound ineffective (20).…”