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Núñez-Otero, Carlos
Publications (3 of 3) Show all publications
Sixt, B. S., Núñez-Otero, C., Kepp, O., Valdivia, R. H. & Kroemer, G. (2019). Chlamydia trachomatis fails to protect its growth niche against pro-apoptotic insults. Cell Death and Differentiation, 26(8), 1485-1500
Open this publication in new window or tab >>Chlamydia trachomatis fails to protect its growth niche against pro-apoptotic insults
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2019 (English)In: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 26, no 8, p. 1485-1500Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is an obligate intracellular bacterial agent responsible for ocular infections and sexually transmitted diseases. It has been postulated that Chlamydia inhibits apoptosis in host cells to maintain an intact replicative niche until sufficient infectious progeny can be generated. Here we report that, while cells infected with C. trachomatis are protected from apoptosis at early and mid-stages of infection, they remain susceptible to the induction of other cell death modalities. By monitoring the fate of infected cells by time-lapse video microscopy and by analyzing host plasma membrane integrity and the activity of caspases, we determined that C. trachomatis-infected cells exposed to pro-apoptotic stimuli predominately died by a mechanism resembling necrosis. This necrotic death of infected cells occurred with kinetics similar to the induction of apoptosis in uninfected cells, indicating that C. trachomatis fails to considerably prolong the lifespan of its host cell when exposed to pro-apoptotic insults. Inhibitors of bacterial protein synthesis partially blocked necrotic death of infected cells, suggesting that the switch from apoptosis to necrosis relies on an active contribution of the bacteria. Tumor necrosis factor alpha (TNF-α)-mediated induction of necrosis in cells infected with C. trachomatis was not dependent on canonical regulators of necroptosis, such as RIPK1, RIPK3, or MLKL, yet was blocked by inhibition or depletion of CASP8. These results suggest that alternative signaling pathways regulate necrotic death in the context of C. trachomatis infections. Finally, consistent with the inability of C. trachomatis to preserve host cell viability, necrosis resulting from pro-apoptotic conditions significantly impaired production of infectious progeny. Taken together, our findings suggest that Chlamydia's anti-apoptotic activities are not sufficient to protect the pathogen's replicative niche.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Microbiology in the medical area
urn:nbn:se:umu:diva-153979 (URN)10.1038/s41418-018-0224-2 (DOI)000480645800009 ()30375511 (PubMedID)
Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2019-08-30Bibliographically approved
Mojica, S. A., Salin, O., Bastidas, R. J., Sunduru, N., Hedenström, M., Andersson, C. D., . . . Gylfe, Å. (2017). N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF. Antimicrobial Agents and Chemotherapy, 61(10), Article ID e00716-17.
Open this publication in new window or tab >>N-acylated derivatives of sulfamethoxazole block Chlamydia fatty acid synthesis and interact with FabF
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2017 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 10, article id e00716-17Article in journal (Refereed) Published
Abstract [en]

The type II fatty acid synthesis (FASII) pathway is essential for bacterial lipid biosynthesis and continues to be a promising target for novel antibacterial compounds. Recently, it has been demonstrated that Chlamydia is capable of FASII and this pathway is indispensable for Chlamydia growth. Previously, a high-content screen with Chlamydia trachomatis-infected cells was performed, and acylated sulfonamides were identified to be potent growth inhibitors of the bacteria. C. trachomatis strains resistant to acylated sulfonamides were isolated by serial passage of a wild-type strain in the presence of low compound concentrations. Results from whole-genome sequencing of 10 isolates from two independent drug-resistant populations revealed that mutations that accumulated in fabF were predominant. Studies of the interaction between the FabF protein and small molecules showed that acylated sulfonamides directly bind to recombinant FabF in vitro and treatment of C. trachomatis-infected HeLa cells with the compounds leads to a decrease in the synthesis of Chlamydia fatty acids. This work demonstrates the importance of FASII for Chlamydia development and may lead to the development of new antimicrobials.

Place, publisher, year, edition, pages
American society for microbiology, 2017
Chlamydia trachomatis, FAS, antimicrobial agents, drug targets
National Category
Microbiology Pharmaceutical Sciences
urn:nbn:se:umu:diva-140637 (URN)10.1128/AAC.00716-17 (DOI)000411481800016 ()
Available from: 2017-10-18 Created: 2017-10-18 Last updated: 2018-06-09Bibliographically approved
Good, J. A. D., Kulén, M., Silver, J., Krishnan, K. S., Bahnan, W., Núñez-Otero, C., . . . Almqvist, F. (2017). Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity. Journal of Medicinal Chemistry, 60(22), 9393-9399
Open this publication in new window or tab >>Thiazolino 2-pyridone amide isosteres as inhibitors of Chlamydia trachomatis infectivity
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2017 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 22, p. 9393-9399Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis is a global health burden due to its prevalence as a sexually transmitted disease and as the causative agent of the eye infection trachoma. We recently discovered 3-amido thiazolino 2-pyridones which attenuated C. trachomatis infectivity without affecting host cell or commensal bacteria viability. We present here the synthesis and evaluation of nonhydrolyzable amide isosteres based on this class, leading to highly potent 1,2,3-triazole based infectivity inhibitors (EC50 ≤ 20 nM).

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Medicinal Chemistry
urn:nbn:se:umu:diva-142974 (URN)10.1021/acs.jmedchem.7b00716 (DOI)000416500200019 ()29053275 (PubMedID)
Available from: 2017-12-14 Created: 2017-12-14 Last updated: 2018-08-28Bibliographically approved

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