Publications by authors named "Teis E Sondergaard"

12 Publications

  • Page 1 of 1

Cyclic, Hydrophobic Hexapeptide Fusahexin Is the Product of a Nonribosomal Peptide Synthetase in .

J Nat Prod 2021 08 22;84(8):2070-2080. Epub 2021 Jul 22.

Department of Chemistry and Bioscience, Aalborg University, Frederik Bajers Vej 7H, DK-9220 Aalborg, Denmark.

The plant pathogenic fungus is known to produce a wide array of secondary metabolites during plant infection. This includes several nonribosomal peptides. Recently, the fusaoctaxin (/9) and gramilin () gene clusters were shown to be induced by host interactions. To widen our understanding of this important pathogen, we investigated the involvement of the gene cluster during infection and oxidative and osmotic stress. Overexpression of led to the discovery of a new cyclic hexapeptide, fusahexin (), with the amino acid sequence cyclo-(d-Ala-l-Leu-d--Thr-l-Pro-d-Leu-l-Leu). The structural analyses revealed an unusual ether bond between a proline C to C of the preceding threonine resulting in an oxazine ring system. The comparative genomic analyses showed that the small gene cluster only encodes an ABC transporter in addition to the five-module nonribosomal peptide synthetase (NRPS). Based on the structure of fusahexin and the domain architecture of , we propose a biosynthetic model in which the terminal module is used to incorporate two leucine units. So far, iterative use of NRPS modules has primarily been described for siderophore synthetases, which makes a rare example of a fungal nonsiderophore NRPS with distinct iterative module usage.
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http://dx.doi.org/10.1021/acs.jnatprod.0c00947DOI Listing
August 2021

Undefeated-Changing the phenamacril scaffold is not enough to beat resistant Fusarium.

PLoS One 2020 29;15(6):e0235568. Epub 2020 Jun 29.

Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.

Filamentous fungi belonging to the genus Fusarium are notorious plant-pathogens that infect, damage and contaminate a wide variety of important crops. Phenamacril is the first member of a novel class of single-site acting cyanoacrylate fungicides which has proven highly effective against important members of the genus Fusarium. However, the recent emergence of field-resistant strains exhibiting qualitative resistance poses a major obstacle for the continued use of phenamacril. In this study, we synthesized novel cyanoacrylate compounds based on the phenamacril-scaffold to test their growth-inhibitory potential against wild-type Fusarium and phenamacril-resistant strains. Our findings show that most chemical modifications to the phenamacril-scaffold are associated with almost complete loss of fungicidal activity and in vitro inhibition of myosin motor domain ATPase activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323951PMC
September 2020

Phenamacril is a reversible and noncompetitive inhibitor of class I myosin.

J Biol Chem 2019 01 30;294(4):1328-1337. Epub 2018 Nov 30.

Department of Chemistry and Bioscience, Aalborg University, DK-9220 Aalborg, Denmark. Electronic address:

The cyanoacrylate compound phenamacril (also known as JS399-19) is a recently identified fungicide that exerts its antifungal effect on susceptible species by inhibiting the ATPase activity of their myosin class I motor domains. Although much is known about the antifungal spectrum of phenamacril, the exact mechanism behind the phenamacril-mediated inhibition remains to be resolved. Here, we describe the characterization of the effect of phenamacril on purified myosin motor constructs from the model plant pathogen and phenamacril-susceptible species , phenamacril-resistant species, and the mycetozoan model organism Our results show that phenamacril potently (IC ∼360 nm), reversibly, and noncompetitively inhibits ATP turnover, actin binding during ATP turnover, and motor activity of myosin-1. Phenamacril also inhibits the ATPase activity of myosin-1 but has little or no inhibitory effect on the motor activity of myosin-1, human myosin-1c, and myosin isoforms 1B, 1E, and 2. Our findings indicate that phenamacril is a species-specific, noncompetitive inhibitor of class I myosin in susceptible sp.
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http://dx.doi.org/10.1074/jbc.RA118.005408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349130PMC
January 2019

Synergistic activities of meropenem double and triple combinations against carbapenemase-producing Enterobacteriaceae.

Diagn Microbiol Infect Dis 2017 Aug 3;88(4):355-360. Epub 2017 May 3.

Department of Clinical Microbiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus, Denmark.

The increasing emergence of carbapenemase-producing Enterobacteriaceae poses a considerable threat to global health as only limited treatment options are available and has therefore led to efforts to discover antibiotic combination regimens effective. The aim of this study was to evaluate in vitro synergistic activity of 10 meropenem double and triple combinations against the 5 most frequently encountered carbapenemases-producing Enterobacteriaceae. Broth microdilution assays showed that the meropenem and ertapenem combination was the most efficient regimen of the double combinations tested (>5-log2 fold decrease). The triple combination of meropenem, polymyxin and rifampin exhibited highest synergistic activity of the triple combinations. The divergent reports on synergistic activity of antibiotic combinations suggest that it may not be possible to predict synergy based on carbapenemase type alone. Consequently, we recommend that in vitro evaluation of synergistic activity of antibiotic combinations against carbapenemase-producing Enterobacteriaceae is performed on every isolate to ensure effective treatment regimens.
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http://dx.doi.org/10.1016/j.diagmicrobio.2017.04.015DOI Listing
August 2017

Real-time imaging of the growth-inhibitory effect of JS399-19 on Fusarium.

Pestic Biochem Physiol 2016 Nov 14;134:24-30. Epub 2016 May 14.

Department of Chemistry and Bioscience, Aalborg University, DK-9220 Aalborg, Denmark.

Real-time imaging was used to study the effects of a novel Fusarium-specific cyanoacrylate fungicide (JS399-19) on growth and morphology of four Fusarium sp. This fungicide targets the motor domain of type I myosin. Fusarium graminearum PH-1, Fusarium solani f. sp. pisi 77-13-4, Fusarium avenaceum IBT8464, and Fusarium avenaceum 05001, which has a K216Q amino-acid substitution at the resistance-implicated site in its myosin type I motor domain, were analyzed. Real-time imaging shows that JS399-19 inhibits fungal growth but not to the extent previously reported. The fungicide causes the hypha to become entangled and unable to extend vertically. This implies that type I myosin in Fusarium is essential for hyphal and mycelia propagation. The K216Q substitution correlates with reduced susceptibility in F. avenaceum.
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http://dx.doi.org/10.1016/j.pestbp.2016.05.002DOI Listing
November 2016

Automated image analysis for quantification of filamentous bacteria.

BMC Microbiol 2015 Nov 4;15:255. Epub 2015 Nov 4.

Department of Biotechnology, Chemistry and Environmental Engineering, Aalborg University, Sohngaardsholmsvej 49, 9000, Aalborg, Denmark.

Background: Antibiotics of the β-lactam group are able to alter the shape of the bacterial cell wall, e.g. filamentation or a spheroplast formation. Early determination of antimicrobial susceptibility may be complicated by filamentation of bacteria as this can be falsely interpreted as growth in systems relying on colorimetry or turbidometry (such as Vitek-2, Phoenix, MicroScan WalkAway). The objective was to examine an automated image analysis algorithm for quantification of filamentous bacteria using the 3D digital microscopy imaging system, oCelloScope.

Results: Three E. coli strains displaying different resistant profiles and differences in filamentation kinetics were used to study a novel image analysis algorithm to quantify length of bacteria and bacterial filamentation. A total of 12 β-lactam antibiotics or β-lactam-β-lactamase inhibitor combinations were analyzed for their ability to induce filamentation. Filamentation peaked at approximately 120 min with an average cell length of 30 μm.

Conclusion: The automated image analysis algorithm showed a clear ability to rapidly detect and quantify β-lactam-induced filamentation in E. coli. This rapid determination of β-lactam-mediated morphological alterations may facilitate future development of fast and accurate AST systems, which in turn will enable early targeted antimicrobial therapy. Therefore, rapid detection of β-lactam-mediated morphological changes may have important clinical implications.
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http://dx.doi.org/10.1186/s12866-015-0583-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632676PMC
November 2015

Receptor kinase-mediated control of primary active proton pumping at the plasma membrane.

Plant J 2014 Dec 25;80(6):951-64. Epub 2014 Oct 25.

Department of Plant and Environmental Science, Center for Membrane Pumps in Cells and Disease - PUMPKIN, Danish National Research Foundation, University of Copenhagen, DK-1871, Frederiksberg, Denmark.

Acidification of the cell wall space outside the plasma membrane is required for plant growth and is the result of proton extrusion by the plasma membrane-localized H+-ATPases. Here we show that the major plasma membrane proton pumps in Arabidopsis, AHA1 and AHA2, interact directly in vitro and in planta with PSY1R, a receptor kinase of the plasma membrane that serves as a receptor for the peptide growth hormone PSY1. The intracellular protein kinase domain of PSY1R phosphorylates AHA2/AHA1 at Thr-881, situated in the autoinhibitory region I of the C-terminal domain. When expressed in a yeast heterologous expression system, the introduction of a negative charge at this position caused pump activation. Application of PSY1 to plant seedlings induced rapid in planta phosphorylation at Thr-881, concomitant with an instantaneous increase in proton efflux from roots. The direct interaction between AHA2 and PSY1R observed might provide a general paradigm for regulation of plasma membrane proton transport by receptor kinases.
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http://dx.doi.org/10.1111/tpj.12680DOI Listing
December 2014

Real-time optical antimicrobial susceptibility testing.

J Clin Microbiol 2013 Jul 17;51(7):2047-53. Epub 2013 Apr 17.

Department of Animal Science, Faculty of Science and Technology, Aarhus University, Tjele, Denmark.

Rapid antibiotic susceptibility testing is in high demand in health care fields as antimicrobial-resistant bacterial strains emerge and spread. Here, we describe an optical screening system (oCelloScope) which, based on time-lapse imaging of 96 bacteria-antibiotic combinations at a time, introduces real-time detection of bacterial growth and antimicrobial susceptibility with imaging material to support the automatically generated graphs. Automated antibiotic susceptibility tests of a monoculture showed statistically significant antibiotic effects within 6 min and within 30 min in complex samples from pigs suffering from catheter-associated urinary tract infections. The oCelloScope system provides a fast high-throughput screening method for detecting bacterial susceptibility that might entail an earlier diagnosis and introduction of appropriate targeted therapy and thus combat the threat from multidrug-resistant pathogenic bacteria. The oCelloScope system can be employed for a broad range of applications within bacteriology and might present new vistas as a point-of-care instrument in clinical and veterinary settings.
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http://dx.doi.org/10.1128/JCM.00440-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3697729PMC
July 2013

Quick guide to polyketide synthase and nonribosomal synthetase genes in Fusarium.

Int J Food Microbiol 2012 Apr 15;155(3):128-36. Epub 2012 Feb 15.

Department of Animal Sciences, Faculty of Science and Technology, Aarhus University, Blichers Allé, Postbox 50, 8830 Tjele, Denmark.

Fusarium species produce a plethora of bioactive polyketides and nonribosomal peptides that give rise to health problems in animals and may have drug development potential. Using the genome sequences for Fusarium graminearum, F. oxysporum, F. solani and F. verticillioides we developed a framework for future polyketide synthases (PKSs) and nonribosomal peptides synthetases (NRPSs) nomenclature assignment and classification. Sequence similarities of the adenylation and ketosynthase domain sequences were used to group the identified NRPS and PKS genes. We present the current state of knowledge of PKS and NRPS genes in sequenced Fusarium species and their known products. With the rapid increase in the number of sequenced fungal genomes a systematic classification will greatly aid the scientific community in obtaining an overview of the number of different NRPS and PKS genes and their potential as producers of known bioactive compounds.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2012.01.018DOI Listing
April 2012

In vitro production of necrotic enteritis toxin B, NetB, by netB-positive and netB-negative Clostridium perfringens originating from healthy and diseased broiler chickens.

Vet Microbiol 2010 Jul 11;144(1-2):231-5. Epub 2010 Jan 11.

Department of Animal Health and Bioscience, Faculty of Agricultural Sciences, Aarhus University, Blichers Alle 20, PO Box 50, DK-8830 Tjele, Denmark.

The Clostridium perfringens necrotic enteritis toxin B, NetB, was recently proposed as a new key virulence factor for the development of necrotic enteritis (NE) in broilers. The aim of the present study was to investigate the presence of the netB gene and the in vitro production of the NetB toxin in a well characterized collection of 48 C. perfringens Type A isolates, obtained from Danish broiler flocks. The investigation revealed netB gene prevalences of approx. 50% and 60% among isolates from diseased (NE) and healthy flocks, respectively. Only minor nucleotide variations were observed between the isolates in the coding sequence (CDS) of the netB gene, and the promoter region was observed to be completely conserved. However, in vitro NetB production was only observed in 4 out of 14 netB-positive C. perfringens isolates recovered from healthy birds, whereas 12 out of 13 netB-positive isolates from NE birds were shown to produce the NetB toxin. It is therefore proposed that genotype, i.e. presence of the netB gene, in itself is inadequate for predicting virulence of C. perfringens, and future investigations should focus on the bacterial phenotypes; the regulatory mechanisms involved in the expression of NetB, and potentially also other toxins, and its implications for the virulence of individual C. perfringens strains.
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http://dx.doi.org/10.1016/j.vetmic.2009.12.036DOI Listing
July 2010

Myeloma cell-induced disruption of bone remodelling compartments leads to osteolytic lesions and generation of osteoclast-myeloma hybrid cells.

Br J Haematol 2010 Feb 16;148(4):551-61. Epub 2009 Nov 16.

Department of Clinical Cell Biology, Vejle Hospital, CSFU-IRS, University of Southern Denmark.

Osteolytic lesions are a hallmark of multiple myeloma. They are due to the hyperactivity of bone resorbing osteoclasts and hypoactivity of bone forming osteoblasts, in response to neighbouring myeloma cells. This study identified a structure that deeply affects this response, because of its impact on the physical organisation of the myeloma cell microenvironment. The proximity between myeloma cells and osteoclasts or osteoblasts was shown to be conditioned by the recently discovered layer of flat cells that separates the osteoclasts and osteoblasts from the bone marrow, by forming a canopy over bone remodelling compartment (BRC). These canopies are frequently disrupted in myeloma, and this disruption correlates with increased proximity and density of myeloma cells. In vitro evidence indicates that this disruption may be due to direct contact between myeloma and BRC canopy cells. Importantly, this disruption and increased proximity and density of myeloma cells coincides with key myeloma-induced bone events, such as osteolytic lesions, impaired bone formation despite increased bone resorption, and fusion of myeloma cells with osteoclasts thereby forming myeloma-osteoclast hybrid cells. These findings strongly support a critical role of BRC canopies in myeloma-induced bone disease. BRC canopies could therefore be considered as a new therapeutic target.
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http://dx.doi.org/10.1111/j.1365-2141.2009.07980.xDOI Listing
February 2010

Energization of transport processes in plants. roles of the plasma membrane H+-ATPase.

Plant Physiol 2004 Sep;136(1):2475-82

Department of Plant Biology, The Royal Veterinary and Agricultural University, DK-1871 Copenhagen, Denmark.

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http://dx.doi.org/10.1104/pp.104.048231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC523315PMC
September 2004
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