Mycolates of Mycobacterium tuberculosis modulate the flow of cholesterol for bacillary proliferation in murine macrophages

The differentiation of macrophages into lipid-filled foam cells is a hallmark of the lung granuloma that forms in patients with active tuberculosis (TB). Mycolic acids (MAs), the abundant lipid virulence factors in the cell wall of Mycobacterium tuberculosis (Mtb), can induce this foam phenotype possibly as a way to perturb host cell lipid homeostasis to support the infection. It is not exactly clear how MAs allow differentiation of foam cells during Mtb infection. Here we investigated how chemically synthetic MAs, each with a defined stereochemistry similar to natural Mtb-associated mycolates, influence cell foamy phenotype and mycobacterial proliferation in murine host macrophages. Using light and laser-scanning-confocal microscopy, we assessed the influence of MA structure first on the induction of granuloma cell types, second on intracellular cholesterol accumulation, and finally on mycobacterial growth. While methoxy-MAs (mMAs) effected multi-vacuolar giant cell formation, keto-MAs (kMAs) induced abundant intracellular lipid droplets that were packed with esterified cholesterol. Macrophages from mice treated with kMA were permissive to mycobacterial growth, whereas cells from mMA treatment were not. This suggests a separate yet key involvement of oxygenated MAs in manipulating host cell lipid homeostasis to establish the state of TB

The synthesis of single enantiomers of α-mycolic acids of M.tuberculosis with alternative cyclopropane stereochemistries

We report the synthesis of three stereoisomers of a mycolic acid from Mycobacterium tuberculosis containing a di-cis-cyclopropane and of two stereoisomers of a mycolic acid containing a proximal trans-cyclopropane and a distal cis-cyclopropane.</jats:p

Minimal Position-Velocity Uncertainty Wave Packets in Relativistic and Non-relativistic Quantum Mechanics

We consider wave packets of free particles with a general energy-momentum dispersion relation $E(p)$. The spreading of the wave packet is determined by the velocity v = \p_p E. The position-velocity uncertainty relation $\Delta x \Delta v \geq {1/2} ||$ is saturated by minimal uncertainty wave packets $\Phi(p) = A \exp(- \alpha E(p) + \beta p)$. In addition to the standard minimal Gaussian wave packets corresponding to the non-relativistic dispersion relation $E(p) = p^2/2m$, analytic calculations are presented for the spreading of wave packets with minimal position-velocity uncertainty product for the lattice dispersion relation $E(p) = - \cos(p a)/m a^2$ as well as for the relativistic dispersion relation $E(p) = \sqrt{p^2 + m^2}$. The boost properties of moving relativistic wave packets as well as the propagation of wave packets in an expanding Universe are also discussed

Sterculic Acid and Its Analogues Are Potent Inhibitors of Toxoplasma gondii

Toxoplasmosis is a serious disease caused by Toxoplasma gondii, one of the most widespread parasites in the world. Lipid metabolism is important in the intracellular stage of T. gondii. Stearoyl-CoA desaturase (SCD), a key enzyme for the synthesis of unsaturated fatty acid is predicted to exist in T. gondii. Sterculic acid has been shown to specifically inhibit SCD activity. Here, we examined whether sterculic acid and its methyl ester analogues exhibit anti-T. gondii effects in vitro. T. gondii-infected Vero cells were disintegrated at 36 hr because of the propagation and egress of intracellular tachyzoites. All test compounds inhibited tachyzoite propagation and egress, reducing the number of ruptured Vero cells by the parasites. Sterculic acid and the methyl esters also inhibited replication of intracellular tachyzoites in HFF cells. Among the test compounds, sterculic acid showed the most potent activity against T. gondii, with an EC(50) value of 36.2 μM, compared with EC(50) values of 248-428 μM for the methyl esters. Our study demonstrated that sterculic acid and its analogues are effective in inhibition of T. gondii growth in vitro, suggesting that these compounds or analogues targeting SCD could be effective agents for the treatment of toxoplasmosis