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ID 118016
著者
Kumagai, Keigo National Institute of Infectious Diseases
Sakai, Shota National Institute of Infectious Diseases
Kataoka, Michiyo National Institute of Infectious Diseases
Kobayashi, Shu University of Tokyo
Hanada, Kentaro National Institute of Infectious Diseases
キーワード
infectious disease
Chlamydia trachomatis
bacterial metabolism
antibiotics
ceramide
sphingolipid
inhibitor
stereoselectivity
CERT
sphingomyelin synthase
資料タイプ
学術雑誌論文
抄録
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.
掲載誌名
International Journal of Molecular Sciences
ISSN
14220067
出版者
MDPI
23
23
開始ページ
14697
発行日
2022-11-24
権利情報
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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出版社版DOI
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フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
理工学系