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1.
Cell ; 186(21): 4583-4596.e13, 2023 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-37725977

RESUMO

The CD1 system binds lipid antigens for display to T cells. Here, we solved lipidomes for the four human CD1 antigen-presenting molecules, providing a map of self-lipid display. Answering a basic question, the detection of >2,000 CD1-lipid complexes demonstrates broad presentation of self-sphingolipids and phospholipids. Whereas peptide antigens are chemically processed, many lipids are presented in an unaltered form. However, each type of CD1 protein differentially edits the self-lipidome to show distinct capture motifs based on lipid length and chemical composition, suggesting general antigen display mechanisms. For CD1a and CD1d, lipid size matches the CD1 cleft volume. CD1c cleft size is more variable, and CD1b is the outlier, where ligands and clefts show an extreme size mismatch that is explained by uniformly seating two small lipids in one cleft. Furthermore, the list of compounds that comprise the integrated CD1 lipidome supports the ongoing discovery of lipid blockers and antigens for T cells.


Assuntos
Antígenos CD1 , Lipídeos , Humanos , Apresentação de Antígeno , Antígenos CD1/química , Antígenos CD1/metabolismo , Lipidômica , Lipídeos/química , Linfócitos T , Motivos de Aminoácidos
2.
Chemistry ; 28(36): e202200883, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35388562

RESUMO

The continuous emergence of antimicrobial resistance is causing a threat to patients infected by multidrug-resistant pathogens. In particular, the clinical use of aminoglycoside antibiotics, broad-spectrum antibacterials of last resort, is limited due to rising bacterial resistance. One of the major resistance mechanisms in Gram-positive and Gram-negative bacteria is phosphorylation of these amino sugars at the 3'-position by O-phosphotransferases [APH(3')s]. Structural alteration of these antibiotics at the 3'-position would be an obvious strategy to tackle this resistance mechanism. However, the access to such derivatives requires cumbersome multi-step synthesis, which is not appealing for pharma industry in this low-return-on-investment market. To overcome this obstacle and combat bacterial resistance mediated by APH(3')s, we introduce a novel regioselective modification of aminoglycosides in the 3'-position via palladium-catalyzed oxidation. To underline the effectiveness of our method for structural modification of aminoglycosides, we have developed two novel antibiotic candidates overcoming APH(3')s-mediated resistance employing only four synthetic steps.


Assuntos
Antibacterianos , Farmacorresistência Bacteriana , Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Fosfotransferases
3.
J Immunol ; 206(6): 1240-1250, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33536255

RESUMO

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.


Assuntos
Antígenos de Bactérias/imunologia , Vacina BCG/administração & dosagem , Glicolipídeos/imunologia , Linfócitos T/imunologia , Tuberculose/prevenção & controle , Adolescente , Animais , Antígenos de Bactérias/metabolismo , Antígenos CD1/metabolismo , Linhagem Celular , Criança , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Glicoproteínas/metabolismo , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Pulmão/citologia , Pulmão/imunologia , Pulmão/microbiologia , Macaca mulatta , Masculino , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Cultura Primária de Células , Linfócitos T/metabolismo , Tuberculose/sangue , Tuberculose/imunologia , Tuberculose/microbiologia
4.
Org Lett ; 22(14): 5622-5626, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32635733

RESUMO

Unprotected 3-keto-saccharides have become readily accessible via site-selective oxidation, but their protection-free functionalization is relatively unexplored. Here we show that protecting groups are obsolete in a variety of stereoselective modifications of our model substrate methyl α-glucopyranoside. This allows the preparation of rare sugars and the installation of click handles and reactive groups. To showcase the applicability of the methodology, maltoheptaose has been converted into a chemical probe, and the rare sugar evalose has been synthesized.

5.
Angew Chem Int Ed Engl ; 59(19): 7555-7560, 2020 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-32067294

RESUMO

In Mycobacterium tuberculosis, mycolic acids and their glycerol, glucose, and trehalose esters ("cord factor") form the main part of the mycomembrane. Despite their first isolation almost a century ago, full stereochemical evaluation is lacking, as is a scalable synthesis required for accurate immunological, including vaccination, studies. Herein, we report an efficient, convergent, gram-scale synthesis of four stereo-isomers of a mycolic acid and its glucose ester. Binding to the antigen presenting protein CD1b and T cell activation studies are used to confirm the antigenicity of the synthetic material. The absolute stereochemistry of the syn-methoxy methyl moiety in natural material is evaluated by comparing its optical rotation with that of synthetic material.


Assuntos
Mycobacterium tuberculosis/química , Ácidos Micólicos/síntese química , Antígenos CD1/química , Membrana Celular/química , Ésteres/síntese química , Glucose/química , Ativação Linfocitária , Estereoisomerismo , Linfócitos T , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/química
6.
Chem Commun (Camb) ; 52(10): 2189-91, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26725590

RESUMO

The catalyst palladium/2,9-CD3-phenanthroline has a 1.8 times higher turnover number than its non-deuterated counterpart in the aerobic alcohol oxidation of methyl glucoside and allows the regioselective oxidation with dioxygen as the terminal oxidant.

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