A Series of Ceramide Analogs Modified at the 1-Position with Potent Activity Against the Intracellular Growth of
            <i>Chlamydia Trachomatis</i>

Saied, Essa M.; Banhart, Sebastian; Bürkle, Sophie E; Heuer, Dagmar

doi:10.4155/fmc.15.126

Cited by 38 publications

(35 citation statements)

References 25 publications

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“…All solvents and reagents used were of highest available purity and purchased from typical suppliers. The d -erythro-sphingosine (d18:1), ceramide C18 (d18:1/18), and ceramide C18:1 (d18:1/18:1) used in this study were synthesized according to previous methods developed by the Arenz laboratory 53 . All other lipids were purchased from Avanti Polar Lipids.…”

Section: Methodsmentioning

confidence: 99%

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

Vasiliauskaité-Brooks

Healey

Rochaix

et al. 2018

Nat Commun

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Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients.

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Section: Methodsmentioning

confidence: 99%

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

Vasiliauskaité-Brooks

Healey

Rochaix

et al. 2018

Nat Commun

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“…pDONR223‐COL4A3BP was a gift from William Hahn & David Root (Addgene plasmid #23569; Johannessen et al, ); primers were obtained from MWG Eurofins. HPA12 used in this study was synthesised according to previous methods developed in our lab (Saied, Banhart, Burkle, Heuer, & Arenz, ; Saied, Diederich, & Arenz, ). BODIPY FL C5‐ceramide complexed to BSA was purchased from Molecular Probes.…”

Section: Methodsmentioning

confidence: 99%

The cellular ceramide transport protein CERT promotesChlamydia psittaciinfection and controls bacterial sphingolipid uptake

Koch-Edelmann

Banhart

Saied

et al. 2017

Cellular Microbiology

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Chlamydiaceae are bacterial pathogens that cause diverse diseases in humans and animals. Despite their broad host and tissue tropism, all Chlamydia species share an obligate intracellular cycle of development and have evolved sophisticated mechanisms to interact with their eukaryotic host cells. Here, we have analysed interactions of the zoonotic pathogen Chlamydia psittaci with a human epithelial cell line. We found that C. psittaci recruits the ceramide transport protein (CERT) to its inclusion. Chemical inhibition and CRISPR/Cas9-mediated knockout of CERT showed that CERT is a crucial factor for C. psittaci infections thereby affecting different stages of the infection including inclusion growth and infectious progeny formation. Interestingly, the uptake of fluorescently labelled sphingolipids in bacteria inside the inclusion was accelerated in CERT-knockout cells indicating that C. psittaci can exploit CERT-independent sphingolipid uptake pathways. Moreover, the CERT-specific inhibitor HPA-12 strongly diminished sphingolipid transport to inclusions of infected CERT-knockout cells, suggesting that other HPA-12-sensitive factors are involved in sphingolipid trafficking to C. psittaci. Further analysis is required to decipher these interactions and to understand their contributions to bacterial development, host range, tissue tropism, and disease outcome.

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“…Interestingly, recent studies demonstrated that the sphingoid base sphingosine is also an important first-line defence of healthy airways against Pseudomonas aeruginosa 11 . Recently, a series of ceramide analogs was synthesized and analysed for the growth inhibitory effect on Chlamydia trachomatis 12 . Moreover, several synthetic dihydrosphingosine analogs have been demonstrated to be active against multi-drug resistant strains of Mycobacterium tuberculosis 13 .…”

Section: Introductionmentioning

confidence: 99%

Antibacterial activity of ceramide and ceramide analogs against pathogenic Neisseria

Bécam

Walter²,

Burgert

et al. 2017

Sci Rep

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Certain fatty acids and sphingoid bases found at mucosal surfaces are known to have antibacterial activity and are thought to play a more direct role in innate immunity against bacterial infections. Herein, we analysed the antibacterial activity of sphingolipids, including the sphingoid base sphingosine as well as short-chain C6 and long-chain C16-ceramides and azido-functionalized ceramide analogs against pathogenic Neisseriae. Determination of the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) demonstrated that short-chain ceramides and a ω-azido-functionalized C6-ceramide were active against Neisseria meningitidis and N. gonorrhoeae, whereas they were inactive against Escherichia coli and Staphylococcus aureus. Kinetic assays showed that killing of N. meningitidis occurred within 2 h with ω–azido-C6-ceramide at 1 X the MIC. Of note, at a bactericidal concentration, ω–azido-C6-ceramide had no significant toxic effect on host cells. Moreover, lipid uptake and localization was studied by flow cytometry and confocal laser scanning microscopy (CLSM) and revealed a rapid uptake by bacteria within 5 min. CLSM and super-resolution fluorescence imaging by direct stochastic optical reconstruction microscopy demonstrated homogeneous distribution of ceramide analogs in the bacterial membrane. Taken together, these data demonstrate the potent bactericidal activity of sphingosine and synthetic short-chain ceramide analogs against pathogenic Neisseriae.

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A Series of Ceramide Analogs Modified at the 1-Position with Potent Activity Against the Intracellular Growth of Chlamydia Trachomatis

Abstract: The structure-activity relationship presented here defines an important step toward the molecular target of this compound class, which is still elusive.

Cited by 38 publications

References 25 publications

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

The cellular ceramide transport protein CERT promotesChlamydia psittaciinfection and controls bacterial sphingolipid uptake

Antibacterial activity of ceramide and ceramide analogs against pathogenic Neisseria

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