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Engström, Patrik
Publications (10 of 10) Show all publications
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
Keywords
Chlamydia trachomatis, FAS, antimicrobial agents, drug targets
National Category
Microbiology Pharmaceutical Sciences
Identifiers
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
Engström, P., Bergström, M., Alfaro, A. C., Krishnan, K. S., Bahnan, W., Almqvist, F. & Bergström, S. (2015). Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication. International Journal of Medical Microbiology, 305(3), 378-382
Open this publication in new window or tab >>Expansion of the Chlamydia trachomatis inclusion does not require bacterial replication
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2015 (English)In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 305, no 3, p. 378-382Article in journal (Refereed) Published
Abstract [en]

Chlamydia trachomatis replication takes place inside of a host cell, exclusively within a vacuole known as the inclusion. During an infection, the inclusion expands to accommodate the increasing numbers of C. trachomatis. However, whether inclusion expansion requires bacterial replication and/or de novo protein synthesis has not been previously investigated in detail. Therefore, using a chemical biology approach, we herein investigated C. trachomatis inclusion expansion under varying conditions in vitro. Under normal cell culture conditions, inclusion expansion correlated with C trachomatis replication. When bacterial replication was inhibited using KSK120: an inhibitor that targets C. trachomatis glucose metabolism, inclusions expanded even in the absence of bacterial replication. In contrast, when bacterial protein synthesis was inhibited using chloramphenicol, expansion of inclusions was blocked. Together, these data suggest that de novo protein synthesis is necessary, whereas bacterial replication is dispensable for C trachomatis inclusion expansion. (C) 2015 The Authors. Published by Elsevier GmbH.

Keywords
Chlamydia trachomatis, Chemical biology, Inclusion expansion, Bacterial replication
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-106141 (URN)10.1016/j.ijmm.2015.02.007 (DOI)000354583900012 ()25771502 (PubMedID)
Available from: 2015-07-13 Created: 2015-07-09 Last updated: 2018-06-07Bibliographically approved
Normark, J., Nelson, M., Engström, P., Andersson, M., Björk, R., Moritz, T., . . . Bergström, S. (2014). Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model. PLoS ONE, 9(7), Article ID e103295.
Open this publication in new window or tab >>Maladjusted Host Immune Responses Induce Experimental Cerebral Malaria-Like Pathology in a Murine Borrelia and Plasmodium Co-Infection Model
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e103295Article in journal (Refereed) Published
Abstract [en]

In the Plasmodium infected host, a balance between pro- and anti-inflammatory responses is required to clear the parasites without inducing major host pathology. Clinical reports suggest that bacterial infection in conjunction with malaria aggravates disease and raises both mortality and morbidity in these patients. In this study, we investigated the immune responses in BALB/c mice, co-infected with Plasmodium berghei NK65 parasites and the relapsing fever bacterium Borrelia duttonii. In contrast to single infections, we identified in the co-infected mice a reduction of L-Arginine levels in the serum. It indicated diminished bioavailability of NO, which argued for a dysfunctional endothelium. Consistent with this, we observed increased sequestration of CD8+ cells in the brain as well over expression of ICAM-1 and VCAM by brain endothelial cells. Co-infected mice further showed an increased inflammatory response through IL-1 beta and TNF-alpha, as well as inability to down regulate the same through IL-10. In addition we found loss of synchronicity of pro- and anti-inflammatory signals seen in dendritic cells and macrophages, as well as increased numbers of regulatory T-cells. Our study shows that a situation mimicking experimental cerebral malaria (ECM) is induced in co-infected mice due to loss of timing and control over regulatory mechanisms in antigen presenting cells.

Place, publisher, year, edition, pages
PLOS ONE, 2014
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-92942 (URN)10.1371/journal.pone.0103295 (DOI)000340028800036 ()
Available from: 2014-09-17 Created: 2014-09-09 Last updated: 2018-06-07Bibliographically approved
Engström, P. (2013). Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Chemical genetics discloses the importance of heme and glucose metabolism in Chlamydia trachomatis pathogenesis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chlamydiae are important human bacterial pathogens with an intracellular life cycle that consists of two distinct bacterial forms, an infectious form (EB) that infects the eukaryotic host cell, and a non-infectious form (RB) that allows intracellular proliferation. To be successful, chlamydiae need to alternate between EB and RB to generate infectious EB’s which are competent to infect new host cells.

Chemical genetics is an attractive approach to study bacterial pathogenesis; in principal this approach relies on an inhibitory compound that specifically inhibits a protein of interest. An obstacle in using this approach is target identification, however whole genome sequencing (WGS) of spontaneous mutants resistant to novel inhibitory compounds has significantly extended the utility of chemical genetic approaches by allowing the identification of their target proteins and/or biological pathways.

In this thesis, a chemical genetics approach is used, I have found that heme and glucose metabolism of C. trachomatis is specifically important for the transition from the RB form to the infectious EB form. Heme and glucose metabolism are both coupled to energy metabolism, which suggests a common link between the RB-to-EB transitions. In connection with the above findings I have developed strategies that enable the isolation of isogenic C. trachomatis mutant strains. These strategies are based on WGS of spontaneous mutant populations and subsequent genotyping of clonal strains isolated from these mutant populations. Experiments with the mutant strains suggest that the uptake of glucose-6-phosphate (G-6-P) regulates the RB-to-EB transition, representing one of the first examples where genetics has been used to study C. trachomatis pathogenesis. Additional experiments with the mutant strains indicate that G-6-P promotes bacterial growth during metabolic stress.

In concert with other findings presented in this thesis, I have fine-tuned methods that could be employed to reveal how novel inhibitory chemical compounds affect chlamydiae. In a broader context, I suggest that C. trachomatis could be used as a model organism to understand how new inhibitory drugs affect other bacterial pathogens.

In addition, I observed that C. pneumoniae infections resulted in generalized bone loss in mice and that these mice display a cytokine profile similar to infected bone cells in vitro. Thus, this study indicates that C. pneumoniae potentially can infect bone cells in vivo, resulting in bone loss, alternatively, the inflammatory responses seen in vivo could be the causative factor of the bone loss observed.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. p. 50
Keywords
Chlamydiae, heme metabolism, glucose metabolism, glucose-6-phosphate, RB-to-EB transition
National Category
Natural Sciences
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-70304 (URN)978-91-7459-673-1 (ISBN)978-91-7459-674-8 (ISBN)
Public defence
2013-06-04, Biomedicinhuset, Byggnad 6A, NUS, sal A5, Plan 0, Umeå universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2013-05-14 Created: 2013-05-13 Last updated: 2018-06-08Bibliographically approved
Engström, P., Nguyen, B. D., Normark, J., Nilsson, I., Bastidas, R. J., Gylfe, Å., . . . Bergström, S. (2013). Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity. Journal of Bacteriology, 195(18), 4221-4230
Open this publication in new window or tab >>Mutations in hemG Mediate Resistance to Salicylidene Acylhydrazides, Demonstrating a Novel Link between Protoporphyrinogen Oxidase (HemG) and Chlamydia trachomatis Infectivity
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2013 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 195, no 18, p. 4221-4230Article in journal (Refereed) Published
Abstract [en]

Salicylidene acylhydrazides (SAHs) inhibit the type III secretion system (T3S) of Yersinia and other Gram-negative bacteria. In addition, SAHs restrict the growth and development of Chlamydia species. However, since the inhibition of Chlamydia growth by SAH is suppressed by the addition of excess iron and since SAHs have an iron-chelating capacity, their role as specific T3S inhibitors is unclear. We investigated here whether SAHs exhibit a function on C. trachomatis that goes beyond iron chelation. We found that the iron-saturated SAH INP0341 (IS-INP0341) specifically affects C. trachomatis infectivity with reduced generation of infectious elementary body (EB) progeny. Selection and isolation of spontaneous SAH-resistant mutant strains revealed that mutations in hemG suppressed the reduced infectivity caused by IS-INP0341 treatment. Structural modeling of C. trachomatis HemG predicts that the acquired mutations are located in the active site of the enzyme, suggesting that IS-INP0341 inhibits this domain of HemG and that protoporphyrinogen oxidase (HemG) and heme metabolism are important for C. trachomatis infectivity.

Place, publisher, year, edition, pages
Washington DC, USA: American Society for Microbiology, 2013
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-80746 (URN)10.1128/JB.00506-13 (DOI)000323649300023 ()
Available from: 2013-10-07 Created: 2013-09-25 Last updated: 2018-06-08Bibliographically approved
Wiklund, P., Nordström, A., Högström, M., Alfredson, H., Engström, P., Gustafsson, T., . . . Nordström, P. (2012). High impact loading on the skeleton is associated with a decrease in glucose levels in young men. Clinical Endocrinology, 77(6), 823-827
Open this publication in new window or tab >>High impact loading on the skeleton is associated with a decrease in glucose levels in young men
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2012 (English)In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 77, no 6, p. 823-827Article in journal (Refereed) Published
Abstract [en]

Objective The skeleton has been suggested to be involved in energy metabolism through osteocalcin (OC), an osteoblast-specific molecule. The objective of this study was to investigate whether high impact exercise stimulating bone formation would lead to changes in glucose and lipid metabolism independent of cardiorespiratory effects, and if OC mediates this association.

Design Prospective intervention study.

Methods Fifty men aged 20-32 years were allocated to an intervention group or a control group. The intervention group completed six different types of jumps in sets of five, with the frequency of these exercises gradually increasing over 8 weeks. At baseline and after 8 weeks, glycerol concentrations were measured in fat tissue as a marker of lipolysis by using microdialysis. Blood samples were assayed for OC and markers of glucose and lipid metabolism. Physical activity was measured using an accelerometer.

Results After adjustment for confounders at baseline and changes in physical activity during the intervention period, the intervention was associated with a decrease in levels of glucose (p = 0.04), adrenalin (p = 0.03) and OC (p=0.04) after adjusting for baseline levels and changes in physical activity. No other differences between the groups were significant, although the trends of the metabolic variables favored the intervention group.

Conclusions The results of this study suggest that high impact loading on the skeleton may affect glucose metabolism independent of the level of aerobic exercise.

Place, publisher, year, edition, pages
Blackwell Publishing, 2012
Keywords
High impact loading, skeleton, osteocalcin, glucose
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-42508 (URN)10.1111/j.1365-2265.2012.04461.x (DOI)
Available from: 2011-04-08 Created: 2011-04-08 Last updated: 2018-06-08Bibliographically approved
Engström, P., Bailey, L., Önskog, T., Bergström, S. & Johansson, J. (2010). A comparative study of RNA and DNA as internal gene expression controls early in the developmental cycle of Chlamydia pneumoniae. FEMS Immunology and Medical Microbiology, 58(2), 244-253
Open this publication in new window or tab >>A comparative study of RNA and DNA as internal gene expression controls early in the developmental cycle of Chlamydia pneumoniae
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2010 (English)In: FEMS Immunology and Medical Microbiology, ISSN 0928-8244, E-ISSN 1574-695X, Vol. 58, no 2, p. 244-253Article in journal (Refereed) Published
Abstract [en]

Many microbial pathogens invade and proliferate within host cells and the molecular mechanism underlying this behavior is currently being revealed for several bacterial species. Testing clinically relevant antibacterial compounds and elucidating their effects on gene expression requires adequate controls, especially when studying genetically intractable organisms such as Chlamydia spp., for which various gene fusions cannot be constructed. Until now, relative mRNA levels in Chlamydia have been measured using different internal gene expression controls, including 16S rRNA, mRNAs, and DNA. Here, we compared the advantages and disadvantages of various internal expression controls during the early phase of Chlamydia pneumoniae development. The relative abundance of target mRNAs varied using the different internal control RNAs. This was partly due to variation in the transcript stability of the RNA species. Also, seven out of nine of the analyzed RNAs increased fivefold or more between 2 and 14 h postinfection, while the amount of DNA and number of cells remained essentially unaltered. Our results suggest that RNA should not be used as a gene expression control during the early phase of Chlamydia development, and that intrinsic bacterial DNA is preferable for that purpose because it is stable, abundant, and its relative amount is generally correlated with bacterial numbers.

Keywords
Chlamydia pneumoniae, gene expression, internal controls, mRNA stabilit
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-32837 (URN)10.1111/j.1574-695X.2009.00631.x (DOI)000274311700011 ()20002746 (PubMedID)
Available from: 2010-03-29 Created: 2010-03-29 Last updated: 2018-06-08Bibliographically approved
Sellstedt, M., Nyberg, A., Rosenbaum, E., Engström, P., Wickström, M., Gullbo, J., . . . Almqvist, F. (2010). Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold. European Journal of Organic Chemistry (32), 6171-6178
Open this publication in new window or tab >>Synthesis and characterization of a multi ring-fused 2-pyridone-based fluorescent scaffold
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2010 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 32, p. 6171-6178Article in journal (Refereed) Published
Abstract [en]

A series of compounds based on a novel fluorescent scaffold have been synthesized. Most of the compounds displayed high quantum yields of fluorescence and unusually long fluorescence lifetimes. HeLa cells were treated with one of the compounds and its use as a fluorescent dye was demonstrated with fluorescence confocal microscopy.

Place, publisher, year, edition, pages
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2010
Keywords
Medicinal chemistry, Heterocycles, Luminescence, Fluorescent probes
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-37882 (URN)10.1002/ejoc.201000796 (DOI)000285041500007 ()
Note
Article first published online 24 September 2010Available from: 2010-11-18 Created: 2010-11-18 Last updated: 2018-06-08Bibliographically approved
Bailey, L., Engström, P., Nordström, A., Bergström, S., Waldenström, A. & Nordström, P. (2008). Chlamydia pneumoniae infection results in generalized bone loss in mice. Microbes and infection, 10(10-11), 1175-1181
Open this publication in new window or tab >>Chlamydia pneumoniae infection results in generalized bone loss in mice
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2008 (English)In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 10, no 10-11, p. 1175-1181Article in journal (Refereed) Published
Keywords
Chlamydia pneumoniae; Bone; Osteoblasts; Bone loss
National Category
Infectious Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-11207 (URN)10.1016/j.micinf.2008.06.010 (DOI)18640288 (PubMedID)
Available from: 2008-11-27 Created: 2008-11-27 Last updated: 2018-06-09Bibliographically approved
Söderberg, J. J., Engström, P. & von Pawel-Rammingen, U. (2008). The intrinsic immunoglobulin g endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains. Infection and Immunity, 76(5), 2183-2188
Open this publication in new window or tab >>The intrinsic immunoglobulin g endopeptidase activity of streptococcal Mac-2 proteins implies a unique role for the enzymatically impaired Mac-2 protein of M28 serotype strains
2008 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 76, no 5, p. 2183-2188Article in journal (Refereed) Published
Abstract [en]

IdeS, a secreted cysteine protease of the important human pathogen Streptococcus pyogenes, interferes with phagocytic killing by specifically cleaving the heavy chain of immunoglobulin G (IgG). Two allelic variants of the enzyme have been described, the IgG-specific endopeptidase, IdeS (or Mac-1) and Mac-2, a protein with only weak IgG endopeptidase activity, which has been suggested to interfere with opsonophagocytosis by blocking Fcgamma receptors of phagocytic cells. However, despite the fact that Mac-2 proteins interact with Fcgamma receptors, no inhibition of reactive oxygen species (ROS) production, opsonophagocytosis, or streptococcal killing by Mac-2 has been reported. In the present study, Mac-2 proteins are shown to contain IgG endopeptidase activity indistinguishable from the enzymatic activity exhibited by IdeS/Mac-1 proteins. The earlier reported weak IgG endopeptidase activity appears to be unique to Mac-2 of M28 serotype strains (Mac-2(M28)) and is most likely due to the formation of a disulfide bond between the catalytic site cysteine and a cysteine residue in position 257 of Mac-2(M28). Furthermore, Mac-2 proteins are shown to inhibit ROS production ex vivo, independently of the IgG endopeptidase activity of the proteins. Inhibition of ROS generation per se, however, was not sufficient to mediate streptococcal survival in bactericidal assays. Thus, in contrast to earlier studies, implicating separate functions for IdeS and Mac-2 protein variants, the current study suggests that Mac-2 and IdeS are bifunctional proteins, combining Fcgamma receptor binding and IgG endopeptidase activity. This finding implies a unique role for Mac-2 proteins of the M28 serotype, since this serotype has evolved and retained a Mac-2 protein lacking IgG endopeptidase activity.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-20795 (URN)10.1128/IAI.01422-07 (DOI)18332209 (PubMedID)
Available from: 2009-03-25 Created: 2009-03-25 Last updated: 2018-06-09Bibliographically approved
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