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Gylfe, Åsa
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Publications (10 of 25) Show all publications
Müller, D. C., Kauppi, A., Edin, A., Gylfe, Å., Sjöstedt, A. B. & Johansson, A. (2019). Phospholipid Levels in Blood during Community-Acquired Pneumonia. PLoS ONE, 14(5), Article ID e0216379.
Open this publication in new window or tab >>Phospholipid Levels in Blood during Community-Acquired Pneumonia
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2019 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0216379Article in journal (Refereed) Published
Abstract [en]

Phospholipids, major constituents of bilayer cell membranes, are present in large amounts in pulmonary surfactant and play key roles in cell signaling. Here, we aim at finding clinically useful disease markers in community-acquired pneumonia (CAP) using comprehensive phospholipid profiling in blood and modeling of changes between sampling time points. Serum samples from 33 patients hospitalized with CAP were collected at admission, three hours after the start of intravenous antibiotics, Day 1 (at 12–24 h), Day 2 (at 36–48 h), and several weeks after recovery. A profile of 75 phospholipid species including quantification of the bioactive lysophosphatidylcholines (LPCs) was determined using liquid chromatography coupled to time-of-flight mass spectrometry. To control for possible enzymatic degradation of LPCs, serum autotaxin levels were examined. Twenty-two of the 33 patients with a clinical diagnosis of CAP received a laboratory-verified CAP diagnosis by microbial culture or microbial DNA detection by qPCR. All major phospholipid species, especially the LPCs, were pronouncedly decreased in the acute stage of illness. Total and individual LPC concentrations increased shortly after the initiation of antibiotic treatment, concentrations were at their lowest 3h after the initiation, and increased after Day 1. The total LPC concentration increased by a change ratio of 1.6–1.7 between acute illness and Day 2, and by a ratio of 3.7 between acute illness and full disease resolution. Autotaxin levels were low in acute illness and showed little changes over time, contradicting a hypothesis of enzymatic degradation causing the low levels of LPCs. In this sample of patients with CAP, the results demonstrate that LPC concentration changes in serum of patients with CAP closely mirrored the early transition from acute illness to recovery after the initiation of antibiotics. LPCs should be further explored as potential disease stage biomarkers in CAP and for their potential physiological role during recovery.

Place, publisher, year, edition, pages
Public Library of Science, 2019
Keywords
Community-acquired pneumonia, phospholipids, infection, diagnosis, metabolomics
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-147058 (URN)10.1371/journal.pone.0216379 (DOI)000467148400025 ()31063483 (PubMedID)
Note

Originally included in thesis in manuscript form 

Available from: 2018-04-25 Created: 2018-04-25 Last updated: 2019-06-12Bibliographically approved
Saleeb, M., Mojica, S., Eriksson, A. U., Andersson, C. D., Gylfe, Å. & Elofsson, M. (2018). Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis. European Journal of Medicinal Chemistry, 143, 1077-1089
Open this publication in new window or tab >>Natural product inspired library synthesis – Identification of 2,3-diarylbenzofuran and 2,3-dihydrobenzofuran based inhibitors of Chlamydia trachomatis
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2018 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 143, p. 1077-1089Article in journal (Refereed) Published
Abstract [en]

A natural product inspired library was synthesized based on 2,3-diarylbenzofuran and 2,3-diaryl-2,3-dihydrobenzofuran scaffolds. The library of forty-eight compounds was prepared by utilizing Pd-catalyzed one-pot multicomponent reactions and ruthenium-catalyzed intramolecular carbenoid C-H insertions. The compounds were evaluated for antibacterial activity in a panel of test systems including phenotypic, biochemical and image-based screening assays. We identified several potent inhibitors that block intracellular replication of pathogenic Chlamydia trachomatis with IC50 ≤ 3 μM. These new C. trachomatis inhibitors can serve as starting points for the development of specific treatments that reduces the global burden of C. trachomatis infections.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
2, 3-diaryl-2, 3-dihydrobenzofuran, 2, 3-diaryl-benzofuran, Antibacterial, Benzofuran, Chlamydia
National Category
Organic Chemistry Biological Sciences
Identifiers
urn:nbn:se:umu:diva-143062 (URN)10.1016/j.ejmech.2017.11.099 (DOI)000428216700089 ()29232584 (PubMedID)
Funder
Swedish Foundation for Strategic Research , SB12-0022Swedish Research Council, 621-2014-4670
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-08-24Bibliographically approved
Mojica, S., Eriksson, A. U., Davis, R. A., Bahnan, W., Elofsson, M. & Gylfe, Å. (2018). Red Fluorescent Chlamydia trachomatis Applied to Live Cell Imaging and Screening for Antibacterial Agents. Frontiers in Microbiology, 9, Article ID 3151.
Open this publication in new window or tab >>Red Fluorescent Chlamydia trachomatis Applied to Live Cell Imaging and Screening for Antibacterial Agents
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2018 (English)In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 3151Article in journal (Refereed) Published
Abstract [en]

In this study, we describe the application of a transformed Chlamydia trachomatis strain constitutively expressing the red fluorescent protein mCherry, to allow real-time monitoring of the infection cycle and screening for agents that block replication of C. trachomatis. The red fluorescent C. trachomatis strain was detected autonomously without antibody staining and was equally susceptible to doxycycline as the wild type strain. A high-throughput screening assay was developed using the transformed strain and automated fluorescence microscopy. The assay was used in a pilot screen of a 349 compound library containing natural products from Australian flora and fauna. Compounds with anti-chlamydial activity were tested for dose response and toxicity to host cells and two non-toxic compounds had 50% effective concentration (EC50) values in the low micromolar range. Natural products are valuable sources for drug discovery and the identified Chlamydia growth inhibition may be starting points for future drug development. Live cell imaging was used to visualize growth of the red fluorescent C. trachomatis strain over time. The screening assay reduced workload and reagents compared to an assay requiring immunostaining and could further be used to monitor the development of Chlamydia inclusions and anti-chlamydial effect in real time.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018
Keywords
Chlamydia trachomatis, high content screening, Australian natural products, antibacterial, anti-chlamydial, mCherry, fluorescence-based screening
National Category
Microbiology
Identifiers
urn:nbn:se:umu:diva-155099 (URN)10.3389/fmicb.2018.03151 (DOI)000453657900001 ()
Funder
Swedish Research Council
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-03-06Bibliographically approved
Gylfe, Å., Cajander, S., Wahab, T. & Angelin, M. (2017). Melioidos: en viktig diagnos vid svår sjukdom efter utlandsresa. Läkartidningen, 114, Article ID ERRR.
Open this publication in new window or tab >>Melioidos: en viktig diagnos vid svår sjukdom efter utlandsresa
2017 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id ERRRArticle in journal (Other academic) Published
Place, publisher, year, edition, pages
Stockholm: , 2017
Keywords
Melioidos
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-143138 (URN)
Available from: 2017-12-18 Created: 2017-12-18 Last updated: 2018-06-09Bibliographically 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
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
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
Identifiers
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
Kauppi, A. M., Edin, A., Ziegler, I., Mölling, P., Sjöstedt, A., Gylfe, Å., . . . Johansson, A. (2016). Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room. PLoS ONE, 11(1), Article ID e0147670.
Open this publication in new window or tab >>Metabolites in Blood for Prediction of Bacteremic Sepsis in the Emergency Room
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0147670Article in journal (Refereed) Published
Abstract [en]

A metabolomics approach for prediction of bacteremic sepsis in patients in the emergency room (ER) was investigated. In a prospective study, whole blood samples from 65 patients with bacteremic sepsis and 49 ER controls were compared. The blood samples were analyzed using gas chromatography coupled to time-of-flight mass spectrometry. Multivariate and logistic regression modeling using metabolites identified by chromatography or using conventional laboratory parameters and clinical scores of infection were employed. A predictive model of bacteremic sepsis with 107 metabolites was developed and validated. The number of metabolites was reduced stepwise until identifying a set of 6 predictive metabolites. A 6-metabolite predictive logistic regression model showed a sensitivity of 0.91(95% CI 0.69-0.99) and a specificity 0.84 (95% CI 0.58-0.94) with an AUC of 0.93 (95% CI 0.89-1.01). Myristic acid was the single most predictive metabolite, with a sensitivity of 1.00 (95% CI 0.85-1.00) and specificity of 0.95 (95% CI 0.74-0.99), and performed better than various combinations of conventional laboratory and clinical parameters. We found that a metabolomics approach for analysis of acute blood samples was useful for identification of patients with bacteremic sepsis. Metabolomics should be further evaluated as a new tool for infection diagnostics.

National Category
Pharmaceutical Sciences Anesthesiology and Intensive Care
Identifiers
urn:nbn:se:umu:diva-130006 (URN)10.1371/journal.pone.0147670 (DOI)000368655300138 ()26800189 (PubMedID)
Available from: 2017-01-11 Created: 2017-01-11 Last updated: 2018-06-09Bibliographically approved
Good, J. A. D., Silver, J., Nunez-Otero, C., Bahnan, W., Krishnan, K. S., Salin, O., . . . Almqvist, F. (2016). Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity. Journal of Medicinal Chemistry, 59(5), 2094-2108
Open this publication in new window or tab >>Thiazolino 2-Pyridone Amide Inhibitors of Chlamydia trachomatis Infectivity
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2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 5, p. 2094-2108Article in journal (Refereed) Published
Abstract [en]

The bacterial pathogen Chlamydia trachomatis is a global health burden currently treated with broad-spectrum antibiotics which disrupt commensal bacteria. We recently identified a compound through phenotypic screening that blocked infectivity of this intracellular pathogen without host cell toxicity (compound 1, KSK 120). Herein, we present the optimization of 1 to a class of thiazolino 2-pyridone amides that are highly efficacious (EC50 <= 100 nM) in attenuating infectivity across multiple serovars of C. trachomatis without host cell toxicity. The lead compound 21a exhibits reduced lipophilicity versus 1 and did not affect the growth or viability of representative commensal flora at 50 mu M. In microscopy studies, a highly active fluorescent analogue 37 localized inside the parasitiphorous inclusion, indicative of a specific targeting of bacterial components. In summary, we present a class of small molecules to enable the development of specific treatments for C. trachomatis.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
National Category
Microbiology in the medical area Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-119066 (URN)10.1021/acs.jmedchem.5b01759 (DOI)000372043400031 ()26849778 (PubMedID)
Available from: 2016-04-20 Created: 2016-04-11 Last updated: 2018-06-07Bibliographically approved
Sunduru, N., Salin, O., Gylfe, Å. & Elofsson, M. (2015). Design, synthesis and evaluation of novel polypharmacological antichlamydial agents. European Journal of Medicinal Chemistry, 101, 595-603
Open this publication in new window or tab >>Design, synthesis and evaluation of novel polypharmacological antichlamydial agents
2015 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 101, p. 595-603Article in journal (Refereed) Published
Abstract [en]

Discovery of new polypharmacological antibacterial agents with multiple modes of actions can be an alternative to combination therapy and also a possibility to slow development of antibiotic resistance. In support to this hypothesis, we synthesized 16 compounds by combining the pharmacophores of Chlamydia trachomatis inhibitors and inhibitors of type III secretion (T3S) in gram-negative bacteria. In this study we have developed salicylidene acylhydrazide sulfonamides (11c & 11d) as new antichlamydial agents that also inhibit T3S in Yersinia pseudotuberculosis.

Keywords
Sulfonamides, Acylhydrazones, Heck coupling, Cyanation, Urea derivatives, Thiourea derivatives, lamydia trachomatis, Chlamydia pneumoniae, Type III secretion system, Antibiotic development
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-109812 (URN)10.1016/j.ejmech.2015.07.019 (DOI)000360771900051 ()26204507 (PubMedID)
Available from: 2015-10-07 Created: 2015-10-06 Last updated: 2018-06-07Bibliographically approved
Bergqvist, J., Forsman, O., Larsson, P., Näslund, J., Lilja, T., Engdahl, C., . . . Bucht, G. (2015). Detection and Isolation of Sindbis Virus from Mosquitoes Captured During an Outbreak in Sweden, 2013. Vector Borne and Zoonotic Diseases, 15(2), 133-140
Open this publication in new window or tab >>Detection and Isolation of Sindbis Virus from Mosquitoes Captured During an Outbreak in Sweden, 2013
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2015 (English)In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 15, no 2, p. 133-140Article in journal (Refereed) Published
Abstract [en]

Mosquito-borne alphaviruses have the potential to cause large outbreaks throughout the world. Here we investigated the causative agent of an unexpected Sindbis virus (SINV) outbreak during August-September, 2013, in a previously nonendemic region of Sweden. Mosquitoes were collected using carbon dioxide-baited CDC traps at locations close to human cases. The mosquitoes were initially screened as large pools by SINV-specific quantitative RT-PCR, and the SINV-positive mosquitoes were species determined by single-nucleotide polymorphism (SNP) analysis, followed by sequencing the barcoding region of the cytochrome oxidase I gene. The proportion of the collected mosquitoes was determined by a metabarcoding strategy. By using novel strategies for PCR screening and genetic typing, a new SINV strain, Lovanger, was isolated from a pool of 1600 mosquitoes composed of Culex, Culiseta, and Aedes mosquitoes as determined by metabarcoding. The SINV-positive mosquito Culiseta morsitans was identified by SNP analysis and sequencing. After whole-genome sequencing and phylogenetic analysis, the SINV Lovanger isolate was shown to be most closely similar to recent Finnish SINV isolates. In conclusion, within a few weeks, we were able to detect and isolate a novel SINV strain and identify the mosquito vector during a sudden SINV outbreak.

Keywords
Barcoding, Mosquito, Isolation, Virus, Sindbis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-100963 (URN)10.1089/vbz.2014.1717 (DOI)000349682500007 ()25700044 (PubMedID)
Available from: 2015-03-18 Created: 2015-03-16 Last updated: 2018-06-07Bibliographically approved
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