Cargando…

Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection

Chlamydia trachomatis (Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need fo...

Descripción completa

Detalles Bibliográficos
Autores principales: Dushime, Rosine, Zhu, Yunhuang, Wu, Hanzhi, Saez, Daniel, Shukla, Kirtikar, Brown-Harding, Heather, Biavatti, Maique W., Nelson, Kimberly J., Poole, Leslie B., Lowther, William T., Jones, Paul B., Furdui, Cristina M., Tsang, Allen W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761737/
https://www.ncbi.nlm.nih.gov/pubmed/33287170
http://dx.doi.org/10.3390/antiox9121220
_version_ 1783627638644932608
author Dushime, Rosine
Zhu, Yunhuang
Wu, Hanzhi
Saez, Daniel
Shukla, Kirtikar
Brown-Harding, Heather
Biavatti, Maique W.
Nelson, Kimberly J.
Poole, Leslie B.
Lowther, William T.
Jones, Paul B.
Furdui, Cristina M.
Tsang, Allen W.
author_facet Dushime, Rosine
Zhu, Yunhuang
Wu, Hanzhi
Saez, Daniel
Shukla, Kirtikar
Brown-Harding, Heather
Biavatti, Maique W.
Nelson, Kimberly J.
Poole, Leslie B.
Lowther, William T.
Jones, Paul B.
Furdui, Cristina M.
Tsang, Allen W.
author_sort Dushime, Rosine
collection PubMed
description Chlamydia trachomatis (Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost treatments. Here we report the activity of spilanthol (SPL), a natural compound with demonstrated anti-inflammatory properties, against Ct infections. Using chemical probes selective for imaging mitochondrial protein sulfenylation and complementary assays, we identify an increase in mitochondrial oxidative state by SPL as the underlying mechanism leading to disruption of host cell F-actin cytoskeletal organization and inhibition of chlamydial infection. The peroxidation product of SPL (SPL endoperoxide, SPL(E)), envisioned to be the active compound in the cellular milieu, was chemically synthesized and showed more potent anti-chlamydial activity. Comparison of SPL and SPL(E) reactivity with mammalian peroxiredoxins, demonstrated preferred reactivity of SPL(E) with Prx3, and virtual lack of SPL reaction with any of the reduced Prx isoforms investigated. Cumulatively, these findings support the function of SPL as a pro-drug, which is converted to SPL(E) in the cellular milieu leading to inhibition of Prx3, increased mitochondrial oxidation and disruption of F-actin network, and inhibition of Ct infection.
format Online
Article
Text
id pubmed-7761737
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-77617372020-12-26 Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection Dushime, Rosine Zhu, Yunhuang Wu, Hanzhi Saez, Daniel Shukla, Kirtikar Brown-Harding, Heather Biavatti, Maique W. Nelson, Kimberly J. Poole, Leslie B. Lowther, William T. Jones, Paul B. Furdui, Cristina M. Tsang, Allen W. Antioxidants (Basel) Article Chlamydia trachomatis (Ct) is a bacterial intracellular pathogen responsible for a plethora of diseases ranging from blindness to pelvic inflammatory diseases and cervical cancer. Although this disease is effectively treated with antibiotics, concerns for development of resistance prompt the need for new low-cost treatments. Here we report the activity of spilanthol (SPL), a natural compound with demonstrated anti-inflammatory properties, against Ct infections. Using chemical probes selective for imaging mitochondrial protein sulfenylation and complementary assays, we identify an increase in mitochondrial oxidative state by SPL as the underlying mechanism leading to disruption of host cell F-actin cytoskeletal organization and inhibition of chlamydial infection. The peroxidation product of SPL (SPL endoperoxide, SPL(E)), envisioned to be the active compound in the cellular milieu, was chemically synthesized and showed more potent anti-chlamydial activity. Comparison of SPL and SPL(E) reactivity with mammalian peroxiredoxins, demonstrated preferred reactivity of SPL(E) with Prx3, and virtual lack of SPL reaction with any of the reduced Prx isoforms investigated. Cumulatively, these findings support the function of SPL as a pro-drug, which is converted to SPL(E) in the cellular milieu leading to inhibition of Prx3, increased mitochondrial oxidation and disruption of F-actin network, and inhibition of Ct infection. MDPI 2020-12-03 /pmc/articles/PMC7761737/ /pubmed/33287170 http://dx.doi.org/10.3390/antiox9121220 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. 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/).
spellingShingle Article
Dushime, Rosine
Zhu, Yunhuang
Wu, Hanzhi
Saez, Daniel
Shukla, Kirtikar
Brown-Harding, Heather
Biavatti, Maique W.
Nelson, Kimberly J.
Poole, Leslie B.
Lowther, William T.
Jones, Paul B.
Furdui, Cristina M.
Tsang, Allen W.
Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title_full Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title_fullStr Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title_full_unstemmed Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title_short Discovery of Spilanthol Endoperoxide as a Redox Natural Compound Active against Mammalian Prx3 and Chlamydia trachomatis Infection
title_sort discovery of spilanthol endoperoxide as a redox natural compound active against mammalian prx3 and chlamydia trachomatis infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761737/
https://www.ncbi.nlm.nih.gov/pubmed/33287170
http://dx.doi.org/10.3390/antiox9121220
work_keys_str_mv AT dushimerosine discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT zhuyunhuang discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT wuhanzhi discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT saezdaniel discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT shuklakirtikar discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT brownhardingheather discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT biavattimaiquew discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT nelsonkimberlyj discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT pooleleslieb discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT lowtherwilliamt discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT jonespaulb discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT furduicristinam discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection
AT tsangallenw discoveryofspilantholendoperoxideasaredoxnaturalcompoundactiveagainstmammalianprx3andchlamydiatrachomatisinfection