Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae
We demonstrate in the current work that small cationic antimicrobial beta(2,2)-amino acid derivatives (Mw <500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (<5 mu M, i.e. <3.4 mu g/mL). C. pneumoniae is an atypical respiratory pathogen associated wi...
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ftunivhelsihelda:oai:helda.helsinki.fi:10138/164951 2024-01-07T09:40:46+01:00 Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae Hanski, Leena Ausbacher, Dominik Tiirola, Terttu M. Strom, Morten B. Vuorela, Pia M. Faculty of Pharmacy Division of Pharmaceutical Biosciences Pharmaceutical Design and Discovery group Explorations of Anti Infectives Drug Research Program 2016-07-25T13:16:02Z 15 application/pdf http://hdl.handle.net/10138/164951 eng eng PUBLIC LIBRARY OF SCIENCE 10.1371/journal.pone.0157306 Academy of Finland (grant 252216 to LH and 272266 to PMV) and Tor, Joe och Pentti Borgs minnesfond are acknowledged for the financial support. The project was further supported by the transition grant of the Faculty of Health Sciences, UiT-The Arctic University of Norway (DA) and the Research Council of Norway, "Fellesloftet", Grant-214493/F20 (MBS). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Hanski , L , Ausbacher , D , Tiirola , T M , Strom , M B & Vuorela , P M 2016 , ' Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae ' , PLoS One , vol. 11 , no. 6 , 0157306 . https://doi.org/10.1371/journal.pone.0157306 ORCID: /0000-0002-3121-8542/work/85118073 84975469760 3cd7883c-745c-40f7-9004-d3ff4daff509 http://hdl.handle.net/10138/164951 000377563000118 cc_by openAccess info:eu-repo/semantics/openAccess IN-VITRO ACTIVITY ANTIMICROBIAL PEPTIDES CHLAMYDOPHILA-PNEUMONIAE DEVELOPMENTAL CYCLE TRACHOMATIS PROTEINS GROWTH CHARGE DRUGS CELLS 317 Pharmacy Article publishedVersion 2016 ftunivhelsihelda 2023-12-14T00:06:15Z We demonstrate in the current work that small cationic antimicrobial beta(2,2)-amino acid derivatives (Mw <500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (<5 mu M, i.e. <3.4 mu g/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the beta(2,2)-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these beta(2,2)-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic beta(2,2)-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-totreat intracellular pathogen. Peer reviewed Article in Journal/Newspaper Arctic HELDA – University of Helsinki Open Repository |
institution |
Open Polar |
collection |
HELDA – University of Helsinki Open Repository |
op_collection_id |
ftunivhelsihelda |
language |
English |
topic |
IN-VITRO ACTIVITY ANTIMICROBIAL PEPTIDES CHLAMYDOPHILA-PNEUMONIAE DEVELOPMENTAL CYCLE TRACHOMATIS PROTEINS GROWTH CHARGE DRUGS CELLS 317 Pharmacy |
spellingShingle |
IN-VITRO ACTIVITY ANTIMICROBIAL PEPTIDES CHLAMYDOPHILA-PNEUMONIAE DEVELOPMENTAL CYCLE TRACHOMATIS PROTEINS GROWTH CHARGE DRUGS CELLS 317 Pharmacy Hanski, Leena Ausbacher, Dominik Tiirola, Terttu M. Strom, Morten B. Vuorela, Pia M. Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
topic_facet |
IN-VITRO ACTIVITY ANTIMICROBIAL PEPTIDES CHLAMYDOPHILA-PNEUMONIAE DEVELOPMENTAL CYCLE TRACHOMATIS PROTEINS GROWTH CHARGE DRUGS CELLS 317 Pharmacy |
description |
We demonstrate in the current work that small cationic antimicrobial beta(2,2)-amino acid derivatives (Mw <500 Da) are highly potent against Chlamydia pneumoniae at clinical relevant concentrations (<5 mu M, i.e. <3.4 mu g/mL). C. pneumoniae is an atypical respiratory pathogen associated with frequent treatment failures and persistent infections. This gram-negative bacterium has a biphasic life cycle as infectious elementary bodies and proliferating reticulate bodies, and efficient treatment is challenging because of its long and obligate intracellular replication cycle within specialized inclusion vacuoles. Chlamydicidal effect of the beta(2,2)-amino acid derivatives in infected human epithelial cells was confirmed by transmission electron microscopy. Images of infected host cells treated with our lead derivative A2 revealed affected chlamydial inclusion vacuoles 24 hours post infection. Only remnants of elementary and reticulate bodies were detected at later time points. Neither the EM studies nor resazurin-based cell viability assays showed toxic effects on uninfected host cells or cell organelles after A2 treatment. Besides the effects on early intracellular inclusion vacuoles, the ability of these beta(2,2)-amino acid derivatives to suppress Chlamydia pneumoniae infectivity upon treatment of elementary bodies suggested also a direct interaction with bacterial membranes. Synthetic beta(2,2)-amino acid derivatives that target C. pneumoniae represent promising lead molecules for development of antimicrobial agents against this hard-totreat intracellular pathogen. Peer reviewed |
author2 |
Faculty of Pharmacy Division of Pharmaceutical Biosciences Pharmaceutical Design and Discovery group Explorations of Anti Infectives Drug Research Program |
format |
Article in Journal/Newspaper |
author |
Hanski, Leena Ausbacher, Dominik Tiirola, Terttu M. Strom, Morten B. Vuorela, Pia M. |
author_facet |
Hanski, Leena Ausbacher, Dominik Tiirola, Terttu M. Strom, Morten B. Vuorela, Pia M. |
author_sort |
Hanski, Leena |
title |
Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
title_short |
Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
title_full |
Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
title_fullStr |
Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
title_full_unstemmed |
Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae |
title_sort |
amphipathic beta(2,2)-amino acid derivatives suppress infectivity and disrupt the intracellular replication cycle of chlamydia pneumoniae |
publisher |
PUBLIC LIBRARY OF SCIENCE |
publishDate |
2016 |
url |
http://hdl.handle.net/10138/164951 |
genre |
Arctic |
genre_facet |
Arctic |
op_relation |
10.1371/journal.pone.0157306 Academy of Finland (grant 252216 to LH and 272266 to PMV) and Tor, Joe och Pentti Borgs minnesfond are acknowledged for the financial support. The project was further supported by the transition grant of the Faculty of Health Sciences, UiT-The Arctic University of Norway (DA) and the Research Council of Norway, "Fellesloftet", Grant-214493/F20 (MBS). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Hanski , L , Ausbacher , D , Tiirola , T M , Strom , M B & Vuorela , P M 2016 , ' Amphipathic beta(2,2)-Amino Acid Derivatives Suppress Infectivity and Disrupt the Intracellular Replication Cycle of Chlamydia pneumoniae ' , PLoS One , vol. 11 , no. 6 , 0157306 . https://doi.org/10.1371/journal.pone.0157306 ORCID: /0000-0002-3121-8542/work/85118073 84975469760 3cd7883c-745c-40f7-9004-d3ff4daff509 http://hdl.handle.net/10138/164951 000377563000118 |
op_rights |
cc_by openAccess info:eu-repo/semantics/openAccess |
_version_ |
1787421562507362304 |