Tetra-
-fluoro-azobenzenes are a class of photoswitches useful for the construction of visible-light-controlled molecular systems. They can be used to achieve spatio-temporal control over the ...properties of a chosen bioactive molecule. However, the introduction of different substituents to the tetra-fluoro-azobenzene core can significantly affect the photochemical properties of the switch and compromise biocompatibility. Herein, we explored the effect of useful substituents, such as functionalization points, attachment handles, and water-solubilizing groups, on the photochemical properties of this photochromic system. In general, all the tested fluorinated azobenzenes exhibited favorable photochemical properties, such as high photostationary state distribution and long half-lives, both in organic solvents and in water. One of the azobenzene building blocks was functionalized with a trehalose group to enable the uptake of the photoswitch into mycobacteria. Following metabolic uptake and incorporation of the trehalose-based azobenzene in the mycobacterial cell wall, we demonstrated photoswitching of the azobenzene in the isolated total lipid extract.
The origin of biomolecular homochirality continues to be one of the most fascinating aspects of prebiotic chemistry. Various amplification strategies for chiral compounds to enhance a small chiral ...preference have been reported, but none of these involves phosphorylation, one of nature's essential chemical reactions. Here we present a simple and robust concept of phosphorylation‐based chiral amplification of amines and amino acids in water. By exploiting the difference in solubility of a racemic phosphoramidate and its enantiopure form, we achieved enantioenrichment in solution. Starting with near racemic, phenylethylamine‐based phosphoramidates, ee's of up to 95 % are reached in a single amplification step. Particularly noteworthy is the enantioenrichment of phosphorylated amino acids and their derivatives, which might point to a potential role of phosphorus en‐route to prebiotic homochirality.
The origin of homochirality is a fundamental scientific question. We show that dissolution behavior of racemic and enantiopure amines can be altered by conversion into phosphoramidates. Stirring a solid scalemic mixture in water leads to enantioenrichment of the solution phase (>90 % ee). Amplification of amino acids and their derivatives show that phosphorylation can serve as a potentially viable source of prebiotic homochirality.
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a ...nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
A palladium‐catalyzed direct synthesis of symmetric biaryl compounds from aryl halides in the presence of tBuLi is described. In situ lithium–halogen exchange generates the corresponding aryl lithium ...reagent, which undergoes a homocoupling reaction with a second molecule of the aryl halide in the presence of the palladium catalyst (1 mol %). The reaction takes place at room temperature, is fast (1 h), and affords the corresponding biaryl compounds in good to excellent yields. The application of the method is demonstrated in an efficient asymmetric total synthesis of mastigophorene A. The chiral biaryl axis is constructed with an atropselectivity of 9:1 owing to catalyst‐induced remote point‐to‐axial chirality transfer.
It takes two: A palladium‐catalyzed direct homocoupling of aryl halides in the presence of tBuLi enabled the synthesis of even tetra‐ortho‐substituted symmetric biaryl compounds in high yield (see scheme). The method was applied to the asymmetric synthesis of mastigophorene A in just eight steps through straightforward enantioselective installation of the benzylic quaternary stereocenter and highly diastereoselective homocoupling.
To identify lipids with roles in tuberculosis disease, we systematically compared the lipid content of virulent Mycobacterium tuberculosis with the attenuated vaccine strain Mycobacterium bovis ...bacillus Calmette–Guérin. Comparative lipidomics analysis identified more than 1,000 molecular differences, including a previously unknown, Mycobacterium tuberculosis- specific lipid that is composed of a diterpene unit linked to adenosine. We established the complete structure of the natural product as 1-tuberculosinyladenosine (1-TbAd) using mass spectrometry and NMR spectroscopy. A screen for 1-TbAd mutants, complementation studies, and gene transfer identified Rv3378c as necessary for 1-TbAd biosynthesi s . Whereas Rv3378c was previously thought to function as a phosphatase, these studies establish its role as a tuberculosinyl transferase and suggest a revised biosynthetic pathway for the sequential action of Rv3377c-Rv3378c. In agreement with this model, recombinant Rv3378c protein produced 1-TbAd, and its crystal structure revealed a cis -prenyl transferase fold with hydrophobic residues for isoprenoid binding and a second binding pocket suitable for the nucleoside substrate. The dual-substrate pocket distinguishes Rv3378c from classical cis -prenyl transferases, providing a unique model for the prenylation of diverse metabolites. Terpene nucleosides are rare in nature, and 1-TbAd is known only in Mycobacterium tuberculosis . Thus, this intersection of nucleoside and terpene pathways likely arose late in the evolution of the Mycobacterium tuberculosis complex; 1-TbAd serves as an abundant chemical marker of Mycobacterium tuberculosis , and the extracellular export of this amphipathic molecule likely accounts for the known virulence-promoting effects of the Rv3378c enzyme.
This work sheds light on the role of the lipid 1-tuberculosinyladenosine in the evolution of an environmental ancestor to
M. tuberculosis
. On a larger scale, it reinforces the importance of ...horizontal gene transfer in bacterial evolution and examines novel models and methods to provide a better understanding of the subtle effects of individual
M. tuberculosis
-specific virulence factors in infection settings that are relevant to the pathogen.
ABSTRACT
Mycobacterium kansasii
is an environmental nontuberculous mycobacterium that causes opportunistic tuberculosis-like disease. It is one of the most closely related species to the
Mycobacterium tuberculosis
complex. Using
M. kansasii
as a proxy for the
M. kansasii
-
M. tuberculosis
common ancestor, we asked whether introducing the
M. tuberculosis
-specific gene pair
Rv3377c-Rv3378c
into
M. kansasii
affects the course of experimental infection. Expression of these genes resulted in the production of an adenosine-linked lipid species, known as 1-tuberculosinyladenosine (1-TbAd), but did not alter growth
in vitro
under standard conditions. Production of 1-TbAd enhanced growth of
M. kansasii
under acidic conditions through a bacterial cell-intrinsic mechanism independent of controlling pH in the bulk extracellular and intracellular spaces. Production of 1-TbAd led to greater burden of
M. kansasii
in the lungs of C57BL/6 mice during the first 24 h after infection, and
ex vivo
infections of alveolar macrophages recapitulated this phenotype within the same time frame. However, in long-term infections, production of 1-TbAd resulted in impaired bacterial survival in both C57BL/6 mice and
Ccr2
−/−
mice. We have demonstrated that
M. kansasii
is a valid surrogate of
M. tuberculosis
to study virulence factors acquired by the latter organism, yet shown the challenge inherent to studying the complex evolution of mycobacterial pathogenicity with isolated gene complementation.
IMPORTANCE
This work sheds light on the role of the lipid 1-tuberculosinyladenosine in the evolution of an environmental ancestor to
M. tuberculosis
. On a larger scale, it reinforces the importance of horizontal gene transfer in bacterial evolution and examines novel models and methods to provide a better understanding of the subtle effects of individual
M. tuberculosis
-specific virulence factors in infection settings that are relevant to the pathogen.
The origin of biomolecular homochirality continues to be one of the most fascinating aspects of prebiotic chemistry. Various amplification strategies for chiral compounds to enhance a small chiral ...preference have been reported, but none of these involves phosphorylation, one of nature's essential chemical reactions. Here we present a simple and robust concept of phosphorylation‐based chiral amplification of amines and amino acids in water. By exploiting the difference in solubility of a racemic phosphoramidate and its enantiopure form, we achieved enantioenrichment in solution. Starting with near racemic, phenylethylamine‐based phosphoramidates, ee's of up to 95 % are reached in a single amplification step. Particularly noteworthy is the enantioenrichment of phosphorylated amino acids and their derivatives, which might point to a potential role of phosphorus en‐route to prebiotic homochirality.
The origin of homochirality is a fundamental scientific question. We show that dissolution behavior of racemic and enantiopure amines can be altered by conversion into phosphoramidates. Stirring a solid scalemic mixture in water leads to enantioenrichment of the solution phase (>90 % ee). Amplification of amino acids and their derivatives show that phosphorylation can serve as a potentially viable source of prebiotic homochirality.
The pathogen Mycobacterium tuberculosis (Mtb), causing tuberculosis disease, features an extraordinary thick cell envelope, rich in Mtb-specific lipids, glycolipids, and glycans. These cell wall ...components are often directly involved in host–pathogen interaction and recognition, intracellular survival, and virulence. For decades, these mycobacterial natural products have been of great interest for immunology and synthetic chemistry alike, due to their complex molecular structure and the biological functions arising from it. The synthesis of many of these constituents has been achieved and aided the elucidation of their function by utilizing the synthetic material to study Mtb immunology. This review summarizes the synthetic efforts of a quarter century of total synthesis and highlights how the synthesis layed the foundation for immunological studies as well as drove the field of organic synthesis and catalysis to efficiently access these complex natural products.
A novel synthesis of the aggregation pheromone of the Colorado potato beetle, Leptinotarsa decemlineata, has been developed based on a Sharpless asymmetric epoxidation in combination with a ...chemoselective alcohol oxidation using catalytic (neocuproine)PdOAc2OTf2. Employing this approach, the pheromone was synthesized in 3 steps, 80% yield and 86% ee from geraniol.
Virgin females of the parasitoid wasp Trichogramma turkestanica produce minute amounts of a sex pheromone, the identity of which has not been fully established. The enantioselective synthesis of a ...putative component of this pheromone, (6S,8S,10S)-4,6,8,10-tetramethyltrideca-2E,4E-dien-1-ol (2), is reported as a contribution to this identification. Catalytic asymmetric conjugate addition of methylmagnesium bromide and stereoselective Horner-Wadsworth-Emmons olefinations are used as the key steps, and 2 was obtained in 16 steps with an overall yield of 4.4%.
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