ID | 118016 |
Author |
Kumagai, Keigo
National Institute of Infectious Diseases
Sakai, Shota
National Institute of Infectious Diseases
Ueno, Masaharu
Tokushima University
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Kataoka, Michiyo
National Institute of Infectious Diseases
Kobayashi, Shu
University of Tokyo
Hanada, Kentaro
National Institute of Infectious Diseases
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Keywords | infectious disease
Chlamydia trachomatis
bacterial metabolism
antibiotics
ceramide
sphingolipid
inhibitor
stereoselectivity
CERT
sphingomyelin synthase
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Content Type |
Journal Article
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Description | The obligate intracellular bacterium Chlamydia trachomatis is the major causative agent of bacterial sexually transmitted diseases worldwide. In infected cells, the ceramide transport protein (CERT) is recruited to inclusions, where C. trachomatis replicates using host-synthesized ceramide. The ceramide is converted to sphingomyelin (SM) by a chlamydial infection-dependent SM synthesis (cidSM-synthesis) pathway, which occurs even in the absence of the SM synthases (SMS)-1 and -2 of host cells. The ceramide mimetic compound (1R,3S)-HPA-12 and the nonmimetic compound E16A, both of which are potent inhibitors of CERT, repressed the proliferation of C. trachomatis in HeLa cells. Unexpectedly, (1R,3R)-HPA-12, a ceramide mimetic compound that lacks CERT inhibitory activity, also exhibited potent anti-chlamydial activity. Using endogenous SMS-knockout mutant HeLa cells, we revealed that (1R,3R)-HPA-12 mildly inhibited cidSM-synthesis. In addition, LC-MS analysis revealed that (1R,3R)-HPA-12 is converted to a phosphocholine-conjugated metabolite in an infection-dependent manner. Imaging analysis with a fluorescent analog of ceramide suggested that cidSM-synthesis occurs in the bacterial bodies and/or inclusions. Collectively, these results suggested that (1R,3R)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of cidSM-synthesis, but also via putative toxic effects of its phosphocholine adduct, which is most likely produced by the cidSM-synthesis route.
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Journal Title |
International Journal of Molecular Sciences
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ISSN | 14220067
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Publisher | MDPI
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Volume | 23
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Issue | 23
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Start Page | 14697
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Published Date | 2022-11-24
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Rights | This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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language |
eng
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Publisher
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departments |
Science and Technology
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