Total Synthesis of a Mycolic Acid from <i>Mycobacterium tuberculosis</i>

Tahiri, Nabil; Fodran, Peter; Jayaraman, Dhineshkumar; Buter, Jeffrey; Witte, Martin D.; Ocampo, Tonatiuh A.; Moody, D. Branch; Rhijn, Ildiko Van; Minnaard, Adriaan J.

doi:10.1002/anie.202000523

Cited by 20 publications

(17 citation statements)

References 30 publications

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“…Mtb possesses an unusual cell wall: Its inner layer is comprised of peptidoglycan, the middle layer of a highly branched AG, and the outer layer of long‐chain mycolic acids (Jankute et al, 2015 ). Both peptidoglycans and mycolic acids are well known as important PAMPs that trigger a cascade of innate immune responses (Korf et al, 2005 ; Verschoor et al, 2012 ; Wolf et al, 2016 ; Wolf & Underhill, 2018 ; Lu et al, 2019 ; Tahiri et al, 2020 ; Bastos et al, 2021 ). AG is an essential component of the hydrophobic and highly impermeable cell wall of Mtb ; however, its biological function remains elusive.…”

Section: Discussionmentioning

confidence: 99%

Sensing of mycobacterial arabinogalactan by galectin‐9 exacerbates mycobacterial infection

Zheng

et al. 2021

EMBO Reports

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Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and biosynthetical target for anti-tuberculosis (TB) drug development.Here, we report that mycobacterial AG is recognized by galectin-9 and exacerbates mycobacterial infection. Administration of AG-specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin-9 with high affinity, and galectin-9 associates with transforming growth factor b-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin-9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators.

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Section: Discussionmentioning

confidence: 99%

Sensing of mycobacterial arabinogalactan by galectin‐9 exacerbates mycobacterial infection

Zheng

et al. 2021

EMBO Reports

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“…C 32 -GMM isolated from Rhodococcus equi, synthetic phosphomycoketide (PM), and diacylated sulfoglycolipid (Ac 2 SGL) were generously provided by the laboratory of D. B. Moody (20,44,45). Synthetic C 80 -GMM was prepared as we recently described (45). Stock GMM, PM, or Ac 2 SGL was solvated in chloroform/methanol (2:1, v/v) at a concentration of 1 mg/ml.…”

Section: Preparation Of Lipid-loaded Cd1 Tetramersmentioning

confidence: 99%

T Cells Specific for a Mycobacterial Glycolipid Expand after Intravenous Bacillus Calmette–Guérin Vaccination

Layton

Barman

Wilburn

et al. 2021

The Journal of Immunology

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Intradermal vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) protects infants from disseminated tuberculosis, and i.v. BCG protects nonhuman primates (NHP) against pulmonary and extrapulmonary tuberculosis. In humans and NHP, protection is thought to be mediated by T cells, which typically recognize bacterial peptide Ags bound to MHC proteins. However, during vertebrate evolution, T cells acquired the capacity to recognize lipid Ags bound to CD1a, CD1b, and CD1c proteins expressed on APCs. It is unknown whether BCG induces T cell immunity to mycobacterial lipids and whether CD1-restricted T cells are resident in the lung. In this study, we developed and validated Macaca mulatta (Mamu) CD1b and CD1c tetramers to probe ex vivo phenotypes and functions of T cells specific for glucose monomycolate (GMM), an immunodominant mycobacterial lipid Ag. We discovered that CD1b and CD1c present GMM to T cells in both humans and NHP. We show that GMM-specific T cells are expanded in rhesus macaque blood 4 wk after i.v. BCG, which has been shown to protect NHP with near-sterilizing efficacy upon M. tuberculosis challenge. After vaccination, these T cells are detected at high frequency within bronchoalveolar fluid and express CD69 and CD103, markers associated with resident memory T cells. Thus, our data expand the repertoire of T cells known to be induced by whole cell mycobacterial vaccines, such as BCG, and show that lipid Ag-specific T cells are resident in the lungs, where they may contribute to protective immunity.

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“…The ( R , R )-configuration of the α-alkyl-β-hydroxy carboxylic acid unit has been shown to be crucial for T-cell recognition of mycolic acids when presented by CD1b . Furthermore, the stereochemistry of the distal α-methyl-methoxy unit is S , S , as proven by synthesis of both diastereomeric forms followed by comparison of their optical rotation with the natural product. ,, The stereochemistry is relevant as it influences the binding of the mycolic acid to CD1b . To date, the absolute stereochemistry of the cis -cyclopropyl group has not been indisputably elucidated, although evidence from CD1b binding studies points toward the ( R , S )-configuration …”

Section: Mycolic Acidsmentioning

confidence: 99%

“…The most recent total synthesis of four diastereoisomers 92a – d of methoxy-mycolic acid was communicated by our laboratory . In order to access the target mycolic acids, a new synthetic strategy was developed involving the synthesis of three main fragments (A–C).…”

Section: Mycolic Acidsmentioning

confidence: 99%

“…67,72,73 The stereochemistry is relevant as it influences the binding of the mycolic acid to CD1b. 73 To date, the absolute stereochemistry of the cis-cyclopropyl group has not been indisputably elucidated, although evidence from CD1b binding studies points toward the (R,S)-configuration. 73 Mycolic acids have been found to exhibit various biological functions.…”

Section: Mycolic Acidsmentioning

confidence: 99%

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Chemical Synthesis of Cell Wall Constituents of Mycobacterium tuberculosis

2021

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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.

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Total Synthesis of a Mycolic Acid from Mycobacterium tuberculosis

Cited by 20 publications

References 30 publications

Sensing of mycobacterial arabinogalactan by galectin‐9 exacerbates mycobacterial infection

Sensing of mycobacterial arabinogalactan by galectin‐9 exacerbates mycobacterial infection

T Cells Specific for a Mycobacterial Glycolipid Expand after Intravenous Bacillus Calmette–Guérin Vaccination

Chemical Synthesis of Cell Wall Constituents of Mycobacterium tuberculosis

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