| 1. |
- Kirsebom, O. S., et al.
(författare)
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Precise and accurate determination of the B-8 decay spectrum
- 2011
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Ingår i: Physical Review C - Nuclear Physics. - 2469-9985 .- 2469-9993. ; 83:6
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Tidskriftsartikel (refereegranskat)abstract
- Accurate measurements of the B-8 neutrino spectrum are important for the interpretation of solar neutrino data. Experimentally, the B-8 neutrino spectrum can be obtained from the measurement of the beta-delayed alpha spectrum. We report on an alpha-alpha coincidence measurement performed at the IGISOL facility in Jyvaskyla, Finland. Our measurement allows extensive cross-checks to be performed and gives a more intense neutrino spectrum at high energies compared to the present standard. The deviation reaches 4% at the end point of the spectrum. Below 11 MeV, the deviation is less than 1%.
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| 2. |
- Hannan, T. J., et al.
(författare)
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Inhibition of cyclooxygenase-2 prevents chronic and recurrent cystitis
- 2014
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 1:1, s. 46-57
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Tidskriftsartikel (refereegranskat)abstract
- The spread of multidrug-resistant microorganisms globally has created an urgent need for novel therapeuticstrategies to combat urinary tract infections (UTIs). Immunomodulatory therapy may provide benefit, as treatmentof mice with dexamethasone during acute UTI improved outcome by reducing the development of chroniccystitis, which predisposes to recurrent infection. Herewe discovered soluble biomarkers engaged inmyeloid celldevelopment and chemotaxis that were predictive of future UTI recurrence when elevated in the sera of youngwomen with UTI. Translation of these findings revealed that temperance of the neutrophil response early duringUTI, and specifically disruption of bladder epithelial transmigration of neutrophils by inhibition ofcyclooxygenase-2, protected mice against chronic and recurrent cystitis. Further, proteomics identified bladderepithelial remodeling consequent to chronic infection that enhances sensitivity to neutrophil damage. Thus, cyclooxygenase-2 expression during acute UTI is a critical molecular trigger determining disease outcome anddrugs targeting cyclooxygenase-2 could prevent recurrent UTI.
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| 3. |
- Kirsebom, O. S., et al.
(författare)
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The 8B neutrino spectrum
- 2010
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Ingår i: 11th Symposium on Nuclei in the Cosmos, NIC 2010; Heidelberg; Germany; 19 July 2010 through 23 July 2010. - 1824-8039.
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Konferensbidrag (refereegranskat)abstract
- Knowledge of the energy spectrum of the neutrinos emitted in the β decay of8B in the Sun is needed to interpret the neutrino spectrum measured on Earth. Experimentally, the 8B neutrino spectrum may be αextracted from the measurement of the β -delayed a spectrum. In this contribution, the results of a recent α-α coincidence measurement are presented and compared to previous measurements. The implications for the neutrino spectrum are clarified.
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| 4. |
- Ohlsson, Jörgen, et al.
(författare)
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Structure–activity relationships of galabioside derivatives as inhibitors of E. coli and S. suis adhesins: nanomolar inhibitors of S. suis adhesins
- 2005
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Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0539 .- 1477-0520. ; 3:5, s. 886-900
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Tidskriftsartikel (refereegranskat)abstract
- Four collections of Gal1-4Gal derivatives were synthesised and evaluated as inhibitors of the PapG class II adhesin of uropathogenic Escherichia coli and of the PN and PO adhesins of Streptococcus suis strains. Galabiosides carrying aromatic structures at C1, methoxyphenyl O-galabiosides in particular, were identified as potent inhibitors of the PapG adhesin. Phenylurea derivatisation at C3 and methoxymethylation at O2 of galabiose provided inhibitors of the S. suis strains type PN adhesin with remarkably high affinities (30 and 50 nM, respectively). In addition, quantitative structure–activity relationship models for E. coli PapG adhesin and S. suis adhesin type PO were developed using multivariate data analysis. The inhibitory lead structures constitute an advancement towards high-affinity inhibitors as potential anti-adhesion therapeutic agents targeting bacterial infections.
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| 5. |
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| 6. |
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| 7. |
- Cegelski, Lynette, et al.
(författare)
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Small-molecule inhibitors target Escherichia coli amyloid biogenesis and biofilm formation
- 2009
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Ingår i: Nature Chemical Biology. - : Nature Publishing Group. - 1552-4450 .- 1552-4469. ; 5:12, s. 913-919
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Tidskriftsartikel (refereegranskat)abstract
- Curli are functional extracellular amyloid fibers produced by uropathogenic Escherichia coli (UPEC) and other Enterobacteriaceae. Ring-fused 2-pyridones, such as FN075 and BibC6, inhibited curli biogenesis in UPEC and prevented the in vitro polymerization of the major curli subunit protein CsgA. The curlicides FN075 and BibC6 share a common chemical lineage with other ring-fused 2-pyridones termed pilicides. Pilicides inhibit the assembly of type1pili, which are required for pathogenesis during urinary tract infection. Notably, the curlicides retained pilicide activities and inhibited both curli-dependent and type 1–dependent biofilms. Furthermore, pretreatment of UPEC with FN075 significantly attenuated virulence in a mouse model of urinary tract infection. Curli and type 1pili exhibited exclusive and independent roles in promoting UPEC biofilms, and curli provided a fitness advantage in vivo. Thus, the ability of FN075 to block the biogenesis of both curli and type 1pili endows unique anti-biofilm and anti-virulence activities on these compounds.
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| 8. |
- Eifert, S, et al.
(författare)
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Applying the Gender Lens to Risk Factors and Outcome after Adult Cardiac Surgery
- 2014
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Ingår i: Viszeralmedizin. - : S. Karger AG. - 1662-6664. ; 30:2, s. 99-106
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background: </i></b>Applying the gender lens to risk factors and outcome after adult cardiac surgery is of major clinical interest, as the inclusion of sex and gender in research design and analysis may guarantee more comprehensive cardiovascular science and may consecutively result in a more effective surgical treatment as well as cost savings in cardiac surgery. <b><i>Methods: </i></b>We have reviewed classical cardiovascular risk factors (diabetes, arterial hypertension, hyperlipidemia, smoking) according to a gender-based approach. Furthermore, we have examined comorbidities such as depression, renal insufficiency, and hormonal influences in regard to gender. Gender-sensitive economic aspects have been evaluated, surgical outcome has been analyzed, and cardiovascular research has been considered from a gender perspective. <b><i>Results: </i></b>The influence of typical risk factors and outcome after cardiac surgery has been evaluated from a gender perspective, and the gender-specific distribution of these risk factors is reported on. The named comorbidities are listed. Economic aspects demonstrated a gender gap. Outcome after coronary and valvular surgeries as well as after heart transplantation are displayed in this regard. Results after postoperative use of intra-aortic balloon pump are shown. Gender-related aspects of clinical and biomedical cardiosurgical research are reported. <b><i>Conclusions: </i></b>Female gender has become an independent risk factor of survival after the majority of cardiosurgical procedures. Severely impaired left ventricular ejection fraction independently predicts survival in men, whereas age does in females.
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| 9. |
- Greene, Sarah E., et al.
(författare)
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Pilicide ec240 Disrupts Virulence Circuits in Uropathogenic Escherichia coli
- 2014
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Ingår i: mBio. - 2161-2129 .- 2150-7511. ; 5:6, s. UNSP e02038-
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Tidskriftsartikel (refereegranskat)abstract
- Chaperone-usher pathway (CUP) pili are extracellular organelles produced by Gram-negative bacteria that mediate bacterial pathogenesis. Small-molecule inhibitors of CUP pili, termed pilicides, were rationally designed and shown to inhibit type 1 or P piliation. Here, we show that pilicide ec240 decreased the levels of type 1, P, and S piliation. Transcriptomic and proteomic analyses using the cystitis isolate UTI89 revealed that ec240 dysregulated CUP pili and decreased motility. Paradoxically, the transcript levels of P and S pilus genes were increased during growth in ec240, even though the level of P and S piliation decreased. In contrast, the most downregulated transcripts after growth in ec240 were from the type 1 pilus genes. Type 1 pilus expression is controlled by inversion of the fimS promoter element, which can oscillate between phase on and phase off orientations. ec240 induced the fimS phase off orientation, and this effect was necessary for the majority of ec240's inhibition of type 1 piliation. ec240 increased levels of the transcriptional regulators SfaB and PapB, which were shown to induce the fimS promoter phase off orientation. Furthermore, the effect of ec240 on motility was abolished in the absence of the SfaB, PapB, SfaX, and PapX regulators. In contrast to the effects of ec240, deletion of the type 1 pilus operon led to increased S and P piliation and motility. Thus, ec240 dysregulated several uropathogenic Escherichia coli (UPEC) virulence factors through different mechanisms and independent of its effects on type 1 pilus biogenesis and may have potential as an antivirulence compound. IMPORTANCE CUP pili and flagella play active roles in the pathogenesis of a variety of Gram-negative bacterial infections, including urinary tract infections mediated by UPEC. These are extremely common infections that are often recurrent and increasingly caused by antibiotic-resistant organisms. Preventing piliation and motility through altered regulation and assembly of these important virulence factors could aid in the development of novel therapeutics. This study increases our understanding of the regulation of these virulence factors, providing new avenues by which to target their expression.
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| 10. |
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| 11. |
- Larsson, Andreas, et al.
(författare)
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Quantitative studies of the binding of the class II PapG adhesin from uropathogenic Escherichia coli to oligosaccharides.
- 2003
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 11:10, s. 2255-2261
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Tidskriftsartikel (refereegranskat)abstract
- Binding of the class II PapG adhesin, found at the tip of filamentous pili on Escherichia coli, to the carbohydrate moiety of globoseries glycolipids in the human kidney is a key step in development of pyelonephritis, a severe form of urinary tract infection. An assay based on surface plasmon resonance for quantification of the binding of the class II PapG adhesin to oligosaccharides has been developed. Using this assay dissociation constants ranging from 80 to 540 M were determined for binding of the PapG adhesin to di-pentasaccharide fragments from the globoseries of glycolipids. A series of galabiose derivatives, modified at the anomeric position, O-2′ or O-3′, was also investigated. The anomeric position appeared to be the most promising for development of improved inhibitors of PapG-mediated adhesion of E. coli. p-Methoxyphenyl galabioside was found to be most potent (Kd=140 M), and binds to PapG almost as well as the Forssman pentasaccharide.
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| 12. |
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| 13. |
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| 14. |
- Maegdefessel, L, et al.
(författare)
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miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 5214-
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Tidskriftsartikel (refereegranskat)abstract
- Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.
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| 15. |
- Matic, L. P., et al.
(författare)
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Novel Multiomics Profiling of Human Carotid Atherosclerotic Plaques and Plasma Reveals Biliverdin Reductase B as a Marker of Intraplaque Hemorrhage
- 2018
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Ingår i: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 3:4, s. 464-480
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Tidskriftsartikel (refereegranskat)abstract
- Clinical tools to identify individuals with unstable atherosclerotic lesions are required to improve prevention of myocardial infarction and ischemic stroke. Here, a systems-based analysis of atherosclerotic plaques and plasma from patients undergoing carotid endarterectomy for stroke prevention was used to identify molecular signatures with a causal relationship to disease. Local plasma collected in the lesion proximity following clamping prior to arteriotomy was profiled together with matched peripheral plasma. This translational workflow identified biliverdin reductase B as a novel marker of intraplaque hemorrhage and unstable carotid atherosclerosis, which should be investigated as a potential predictive biomarker for cardiovascular events in larger cohorts.
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| 16. |
- Nowak-Sliwinska, Patrycja, et al.
(författare)
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Consensus guidelines for the use and interpretation of angiogenesis assays
- 2018
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Ingår i: Angiogenesis. - : Springer. - 0969-6970 .- 1573-7209. ; 21:3, s. 425-532
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Forskningsöversikt (refereegranskat)abstract
- The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
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| 17. |
- Omattage, Natalie S., et al.
(författare)
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Structural basis for usher activation and intramolecular subunit transfer in P pilus biogenesis in Escherichia coli
- 2018
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Ingår i: Nature Microbiology. - : NATURE PUBLISHING GROUP. - 2058-5276. ; 3:12, s. 1362-1368
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Tidskriftsartikel (refereegranskat)abstract
- Chaperone-usher pathway pili are extracellular proteinaceous fibres ubiquitously found on Gram-negative bacteria, and mediate host-pathogen interactions and biofilm formation critical in pathogenesis in numerous human diseases(1). During pilus assembly, an outer membrane macromolecular machine called the usher catalyses pilus biogenesis from the individual subunits that are delivered as chaperone-subunit complexes in the periplasm. The usher orchestrates pilus assembly using all five functional domains: a 24-stranded transmembrane beta-barrel translocation domain, a beta-sandwich plug domain, an amino-terminal periplasmic domain and two carboxy-terminal periplasmic domains (CTD1 and CTD2)(2-6). Despite extensive structural and functional characterization, the mechanism by which the usher is activated to initiate pilus biogenesis is unknown. Here, we present the crystal structure of the full-length PapC usher from Escherichia coli in complex with its cognate PapDG chaperone-subunit complex in a pre-activation state, elucidating molecular details of how the usher is specifically engaged by allosteric interactions with its substrate preceding activation and how the usher facilitates the transfer of subunits from the amino-terminal periplasmic domain to the CTDs during pilus assembly. This work elucidates the intricate workings of a molecular machine that catalyses chaperone-usher pathway pilus assembly and opens the door for the development of potent inhibitors to block pilus biogenesis.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Zommorodi, S, et al.
(författare)
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Understanding abdominal aortic aneurysm epidemiology: socioeconomic position affects outcome
- 2018
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Ingår i: Journal of epidemiology and community health. - : BMJ. - 1470-2738 .- 0143-005X. ; 72:10, s. 904-910
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Tidskriftsartikel (refereegranskat)abstract
- Low socioeconomic position (SEP) has been demonstrated to negatively influence outcome in several cardiovascular patient groups. The aim of this study was to analyse time trends of incidence of intact abdominal aortic aneurysm (iAAA) and ruptured AAA (rAAA), respectively, and to investigate whether SEP had any influence on the probability to present with rupture and, finally, to determine the impact of SEP on outcome.MethodsNationwide population-based study including all individuals with iAAA or rAAA in Sweden during 2001–2015.ResultsThe number of individuals with an AAA was 41 222; the majority were identified as iAAA 33 254 (80.7%) and 7968 (19.3%) as rAAA. Time trends showed decreasing incidence of rAAA but increase in iAAA during the study period. Individuals with low income or low educational level were more likely to present with a rAAA rather than iAAA: OR 2.16 (95 % CI 1.98 to 2.36, p<0.001) and OR 1.33 (95 % CI 1.21 to 1.46, p<0.001), respectively. Low income was also associated with increased 90-day mortality and 1-year mortality after treatment for rAAA, OR 1.42 (95% CI 1.07 to 1.89, p=0.014) and OR 1.39 (95% CI 1.13 to 1.97, p=0.005).ConclusionThis large nationwide study showed a decreasing incidence of rAAA. Individuals with low SEP were found to have an augmented risk of presenting with rAAA rather than iAAA and, in addition, to fare worse after repair. Consequently, SEP should be regarded as a relevant risk factor that should be included in considerations for improved care flow of patients with AAA.
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| 22. |
- Ambite, Ines, et al.
(författare)
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Fimbriae reprogram host gene expression - Divergent effects of P and type 1 fimbriae
- 2019
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 15:6, s. 1007671-1007671
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Tidskriftsartikel (refereegranskat)abstract
- Pathogens rely on a complex virulence gene repertoire to successfully attack their hosts. We were therefore surprised to find that a single fimbrial gene reconstitution can return the virulence-attenuated commensal strain Escherichia coli 83972 to virulence, defined by a disease phenotype in human hosts. E. coli 83972pap stably reprogrammed host gene expression, by activating an acute pyelonephritis-associated, IRF7-dependent gene network. The PapG protein was internalized by human kidney cells and served as a transcriptional agonist of IRF-7, IFN-β and MYC, suggesting direct involvement of the fimbrial adhesin in this process. IRF-7 was further identified as a potent upstream regulator (-log (p-value) = 61), consistent with the effects in inoculated patients. In contrast, E. coli 83972fim transiently attenuated overall gene expression in human hosts, enhancing the effects of E. coli 83972. The inhibition of RNA processing and ribosomal assembly indicated a homeostatic rather than a pathogenic end-point. In parallel, the expression of specific ion channels and neuropeptide gene networks was transiently enhanced, in a FimH-dependent manner. The studies were performed to establish protective asymptomatic bacteriuria in human hosts and the reconstituted E. coli 83972 variants were developed to improve bacterial fitness for the human urinary tract. Unexpectedly, P fimbriae were able to drive a disease response, suggesting that like oncogene addiction in cancer, pathogens may be addicted to single super-virulence factors.
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| 23. |
- Andersson, Jan, et al.
(författare)
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Traffic safety effects when overtaking 30 meter trucks
- 2012
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Ingår i: Advances in Human Factors and Ergonomics 2012- 14 Volume Set. - : Taylor & Francis. - 146655262X - 9781466552623
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Konferensbidrag (refereegranskat)abstract
- The purpose of this paper is to investigate if the introduction of extra-long and heavy trucks has an effect on traffic safety on Swedish roads, especially in relation to overtaking maneuvers. Traffic safety effects will be measured in terms of road user behavior concerning accelerations and time slots. First, focus group interviews with heavy truck drivers. Truck drivers that do not drive extra-long trucks believe that the introduction of extra-long trucks will create a number of traffic safety problems especially in terms of conflicts with ordinary road users. The drivers of extra-long trucks do not experience the problems that ordinary truck drivers predict. The problems they experience can be taken care of with more planning (thinking ahead). They also believe that the traffic sign on the back of the extra-long vehicle has a positive effect. The truck company, working environment and truck equipment are other important aspects mentioned by the drivers of the extra-long vehicles.The simulator study investigates overtaking situations on a 2+1-lane highway, with extra-long trucks (30.4 m) and ordinary trucks (18.75 m). The results reveal that the distance from the rear/front of the truck to the point where only one lane exists affects car drivers’ decision to overtake, independently of truck length. If the truck is in the relatively same position, the timeslot for a safe overtaking maneuver before next one-lane section was reduced significantly for extra-long trucks compared to ordinary trucks. The conclusion is that there exist small tendencies which point in the direction of enhanced traffic safety problems with the introduction of extra-long trucks. The results should, however, be interpreted with caution as the number of data points was few and collected in specific situations and in specific conditions. It was neither considered how the introduction of longer and heavier trucks, given a constant amount of goods, reduces the number of heavy trucks on the road network.
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| 24. |
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| 25. |
- Chorell, Erik, 1980-, et al.
(författare)
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Design and synthesis of C-2 substituted Thiazolo and Dihydrothiazolo ring-fused 2-Pyridones : pilicides with increased antivirulence activity
- 2010
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Ingår i: Journal of Medicinal Chemistry. - Washington, USA : American Chemical Society. - 0022-2623 .- 1520-4804. ; 53:15, s. 5690-5695
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides block pili formation by binding to pilus chaperones and blocking their function in the chaperone/usher pathway in E. coli. Various C-2 substituents were introduced on the pilicide scaffold by design and synthetic method developments. Experimental evaluation showed that proper substitution of this position affected the biological activity of the compound. Aryl substituents resulted in pilicides with significantly increased potencies as measured in pili-dependent biofilm and hemagglutination assays. The structural basis of the PapD chaperone-pilicide interactions was determined by X-ray crystallography.
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| 26. |
- Chorell, Erik, et al.
(författare)
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Design and Synthesis of Fluorescent Pilicides and Curlicides : Bioactive Tools to Study Bacterial Virulence Mechanisms
- 2012
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Ingår i: Chemistry - A European Journal. - Berlin : Wiley-VCH Verlagsgesellschaft. - 0947-6539 .- 1521-3765. ; 18:15, s. 4522-4532
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides and curlicides are compounds that block the formation of the virulence factors pili and curli, respectively. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores. Several of the resulting fluorescent compounds had improved activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated with the bacteria with a heterogeneous distribution.
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| 27. |
- Chorell, Erik, 1980-, et al.
(författare)
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Design and synthesis of fluorescently labeled pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Pilicides and curlicides block formation of the E. coli virulence factors pili and curli. To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized. This was achieved using a strategy where key pilicide and curlicide substituents were replaced by fluorophores having similar physicochemical properties. The resulting fluorescent compounds had improved anti-virulence activities as measured in pili- and curli-dependent biofilm assays. We created fluorescent pilicides and curlicides by introducing both coumarin and 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide scaffold. Fluorescence images of the uropathogenic Escherichia coli (UPEC) strain UTI89 grown in the presence of these compounds shows that the compounds are strongly associated to the bacteria and seem to discriminate between different bacteria in a population.
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| 28. |
- Chorell, Erik, et al.
(författare)
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Mapping pilicide anti-virulence effect in Escherichia coli, a comprehensive structure-activity study
- 2012
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier. - 0968-0896 .- 1464-3391. ; 20:9, s. 3128-3142
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides prevent pili formation and thereby the development of bacterial biofilms in Escherichia coli. We have performed a comprehensive structure activity relationship (SAR) study of the dihydrothiazolo ring-fused 2-pyridone pilicide central fragment by varying all open positions. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) was used to distinguish active from inactive compounds in which polarity proved to be the most important factor for discrimination. A quantitative SAR (QSAR) partial least squares (PLS) model was calculated on the active compounds for prediction of biofilm inhibition activity. In this model, compounds with high inhibitory activity were generally larger, more lipophilic, more flexible and had a lower HOMO. Overall, this resulted in both highly valuable SAR information and potent inhibitors of type 1 pili dependent biofilm formation. The most potent biofilm inhibitor had an EC(50) of 400nM.
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| 29. |
- Chorell, Erik, et al.
(författare)
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Synthesis and application of a bromomethyl substituted scaffold to be used for efficient optimization of anti-virulence activity
- 2011
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier Masson SAS. - 0223-5234 .- 1768-3254. ; 46:4, s. 1103-1116
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Tidskriftsartikel (refereegranskat)abstract
- Pilicides are a class of compounds that attenuate virulence in Gram negative bacteria by blocking the chaperone/usher pathway in Escherichia coli. It has also been shown that compounds derived from the peptidomimetic scaffold that the pilicides are based on can prevent both Aβ aggregation and curli formation. To facilitate optimizations towards the different targets, a new synthetic platform has been developed that enables fast and simple introduction of various substituents in position C-7 on the peptidomimetic scaffold. Importantly, this strategy also enables introduction of previously unattainable heteroatoms in this position. Pivotal to the synthetic strategy is the synthesis of a C-7 bromomethyl substituted derivative of the ring-fused dihydrothiazolo 2-pyridone pilicide scaffold. From this versatile and reactive intermediate various heteroatom-linked substituents could be introduced on the scaffold including amines, ethers, amides and sulfonamides. In addition, carbon-carbon bonds could be introduced to the sp(3)-hybridized bromomethyl substituted scaffold by Suzuki-Miyaura cross couplings. Evaluation of the 24 C-7 substituted compounds in whole-bacterial assays provided important structure-activity data and resulted in the identification of a number of new pilicides with activity as good or better than those developed previously.
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| 30. |
- Dang, Hung The, et al.
(författare)
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Syntheses and biological evaluation of 2-amino-3-acyl-tetrahydrobenzothiophene derivatives : antibacterial agents with antivirulence activity
- 2014
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Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 12:12, s. 1942-1956
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Tidskriftsartikel (refereegranskat)abstract
- Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17 500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.
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| 31. |
- Emtenäs, Hans, et al.
(författare)
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Design and Parallel Solid Phase Synthesis of Ring Fused 2-Pyridinones that Target Pilus Biogenesis in Pathogenic Bacteria
- 2002
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Ingår i: Journal of Combinatorial Chemistry. - : American Chemical Society (ACS). - 1520-4766 .- 1520-4774. ; 4, s. 630-639
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Tidskriftsartikel (refereegranskat)abstract
- A new method for the solid-phase synthesis of enantiomerically enriched highly substituted ring-fused 2-pyridinones 13 has been developed. The synthesis mediates introduction of substituents at two positions in the 2-pyridinone ring in a diverse manner and is suitable for parallel synthesis. 19F NMR spectroscopy was used as a tool to monitor each of the five steps in the reaction sequence. The optimized conditions thus obtained were then used to prepare a library of 20 2-pyridinones with high yields. The library members were chosen from a statistical multivariate design to ensure diversity and reliable data for structure−activity relationships. Screening of the library against the bacterial periplasmic chaperone PapD was performed using surface plasmon resonance. Three new 2-pyridinones with a higher affinity for the chaperone PapD than the previous best 13{10,1} were found, and important structural features could be deduced.
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| 32. |
- Emtenäs, Hans, et al.
(författare)
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Stereoselective synthesis of optically active bicyclic -lactam carboxylic acids that target pilus biogenesis in pathogenic bacteria
- 2003
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Ingår i: Organic & Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 1, s. 1308-14
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Tidskriftsartikel (refereegranskat)abstract
- Optically active bicyclic -lactams were synthesized, starting from 2-H-2-thiazolines and Meldrum's acid derivatives. Several methods to accomplish an ester hydrolysis without damaging the -lactam framework were investigated. A rapid CsOH saponification of the -lactam methyl esters was developed and protonation of the Cs-carboxylates by Amberlite (IR-120 H+) afforded a series of bicyclic -lactam carboxylic acids. Moreover, a convenient method for the synthesis of 2-H-2-thiazolinecarboxylic acid methyl ester 2 was developed. Bicyclic -lactam carboxylic acids 7a–g and aldehydes 4a–d were screened for their affinity to the bacterial periplasmic chaperone PapD using a surface plasmon resonance technique. -Lactams substituted with large acyl substituents showed better binding to the chaperone than the native C-terminal peptide PapG 8, demonstrating that bicyclic -lactams constitute a new class of potential bacterial chaperone inhibitors.
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| 33. |
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| 34. |
- Hedenström, Mattias, et al.
(författare)
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NMR studies of interactions between periplasmic chaperones from uropathogenic E-coli and pilicides that interfere with chaperone function and pilus assembly
- 2005
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Ingår i: ORGANIC & BIOMOLECULAR CHEMISTRY. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 3:23, s. 4193-4200
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of uropathogenic Escherichia coli to host tissue is mediated by pili, which are hair-like protein structures extending from the outer cell membrane of the bacterium. The chaperones FimC and PapD are key components in pilus assembly since they catalyse folding of subunits that are incorporated in type 1 and P pili, respectively, and also transport the subunits across the periplasmic space. Recently, compounds that inhibit pilus biogenesis and interfere with chaperone-subunit interactions have been discovered and termed pilicides. In this paper NMR spectroscopy was used to study the interaction of different pilicides with PapD and FimC in order to gain structural knowledge that would explain the effect that some pilicides have on pilus assembly. First relaxation-edited NMR experiments revealed that the pilicides bound to the PapD chaperone with mM affinity. Then the pilicide-chaperone interaction surface was investigated through chemical shift mapping using N-15-labelled FimC. Principal component analysis performed on the chemical shift perturbation data revealed the presence of three binding sites on the surface of FimC, which interacted with three different classes of pilicides. Analysis of structure-activity relationships suggested that pilicides reduce pilus assembly in E. coli either by binding in the cleft of the chaperone, or by influencing the orientation of the flexible F1-G1 loop, both of which are part of the surface by which the chaperone forms complexes with pilus subunits. It is suggested that binding to either of these sites interferes with folding of the pilus subunits, which occurs during formation of the chaperone-subunit complexes. In addition, pilicides that influence the F1-G1 loop also appear to reduce pilus formation by their ability to dissociate chaperone-subunit complexes.
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| 35. |
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| 36. |
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| 37. |
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| 38. |
- Klinth, Jeanna E, et al.
(författare)
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Impairment of the biomechanical compliance of P pili : a novel means of inhibiting uropathogenic bacterial infections?
- 2012
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Ingår i: European Biophysics Journal. - Berlin : Springer. - 0175-7571 .- 1432-1017. ; 41:3, s. 285-295
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Tidskriftsartikel (refereegranskat)abstract
- Gram-negative bacteria often initiate their colonization by use of extended attachment organelles, so called pili. When exposed to force, the rod of helix-like pili has been found to be highly extendable, mainly attributed to uncoiling and recoiling of its quaternary structure. This provides the bacteria with the ability to redistribute an external force among a multitude of pili, which enables them to withstand strong rinsing flows, which, in turn, facilitates adherence and colonization processes critical to virulence. Thus, pili fibers are possible targets for novel antibacterial agents. By use of a substance that compromises compliance of the pili, the ability of bacteria to redistribute external forces can be impaired, so they will no longer be able to resist strong urine flow and thus be removed from the host. It is possible such a substance can serve as an alternative to existing antibiotics in the future or be a part of a multi-drug. In this work we investigated whether it is possible to achieve this by targeting the recoiling process. The test substance was purified PapD. The effect of PapD on the compliance of P pili was assessed at the single organelle level by use of force-measuring optical tweezers. We showed that the recoiling process, and thus the biomechanical compliance, in particular the recoiling process, can be impaired by the presence of PapD. This leads to a new concept in the search for novel drug candidates combating uropathogenic bacterial infections-"coilicides", targeting the subunits of which the pilus rod is composed.
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| 39. |
- Larsson, Andreas, et al.
(författare)
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Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:4, s. 935-945
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Tidskriftsartikel (refereegranskat)abstract
- A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein(-)protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.
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| 40. |
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| 41. |
- Nye, Taylor M., et al.
(författare)
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Ring-fused 2-pyridones effective against multidrug-resistant Gram-positive pathogens and synergistic with standard-of-care antibiotics
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : PNAS. - 0027-8424 .- 1091-6490. ; 119:43
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Tidskriftsartikel (refereegranskat)abstract
- The alarming rise of multidrug-resistant Gram-positive bacteria has precipitated a healthcare crisis, necessitating the development of new antimicrobial therapies. Here we describe a new class of antibiotics based on a ring-fused 2-pyridone backbone, which are active against vancomycin-resistant enterococci (VRE), a serious threat as classified by the Centers for Disease Control and Prevention, and other multidrug-resistant Gram-positive bacteria. Ring-fused 2-pyridone antibiotics have bacteriostatic activity against actively dividing exponential phase enterococcal cells and bactericidal activity against nondividing stationary phase enterococcal cells. The molecular mechanism of drug-induced killing of stationary phase cells mimics aspects of fratricide observed in enterococcal biofilms, where both are mediated by the Atn autolysin and the GelE protease. In addition, combinations of sublethal concentrations of ring-fused 2-pyridones and standard-of-care antibiotics, such as vancomycin, were found to synergize to kill clinical strains of VRE. Furthermore, a broad range of antibiotic resistant Gram-positive pathogens, including those responsible for the increasing incidence of antibiotic resistant healthcare-associated infections, are susceptible to this new class of 2-pyridone antibiotics. Given the broad antibacterial activities of ring-fused 2-pyridone compounds against Gram-positive (GmP) bacteria we term these compounds GmPcides, which hold promise in combating the rising tide of antibiotic resistant Gram-positive pathogens.
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| 42. |
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| 43. |
- Pemberton, Nils, et al.
(författare)
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Synthesis and evaluation of dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones - Targeting pilus biogenesis in uropathogenic bacteria
- 2008
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Ingår i: Tetrahedron. - : Elsevier. - 0040-4020 .- 1464-5416. ; 64:40, s. 9368-9376
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Tidskriftsartikel (refereegranskat)abstract
- Dihydrothiazolo ring-fused 2-pyridones have previously been shown to inhibit pilus assembly in uropathogenic Escherichia coli. Methods have now been developed to synthesize both dihydroimidazolo and dihydrooxazolo ring-fused 2-pyridones. To obtain the nitrogen analogs, Cbz-protected imidazolines were reacted with an acyl-Meldrum's acid derivative under acidic conditions. To prepare the oxygen analogs, a one-pot procedure was developed that allowed synthesis of dihydrooxazolo ring-fused 2-pyridones starting from acylated serine derivatives. After hydrolysis to their corresponding carboxylic acids and lithium carboxylates, biological evaluation revealed that the sulfur could be replaced by an oxygen atom and still maintains the ability to inhibit pilus assembly in uropathogenic E. coli. However, introducing a secondary amine instead of oxygen resulted in a substantial decrease in biological activity.
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| 44. |
- Pinkner, Jerome S., et al.
(författare)
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Rationally designed small compounds inhibit pilus biogenesis in uropathogenic bacteria
- 2006
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washtington : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:47, s. 17897-17902
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Tidskriftsartikel (refereegranskat)abstract
- A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone–usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type 1 pili were all reduced by 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone–subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.
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| 45. |
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| 46. |
- Sorelius, Karl, et al.
(författare)
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The Microbiology of Infective Native Aortic Aneurysms in a Population-Based Setting
- 2022
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Ingår i: Annals of Vascular Surgery. - : Elsevier. - 0890-5096 .- 1615-5947. ; 78, s. 112-122
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim was to describe the microbiology of surgically treated infective native (mycotic) aortic aneurysms (INAAs), and associated survival and development of infection-related complications (IRCs). Methods: Data were pooled from 2 nationwide studies on surgically treated patients with INAAs in Sweden, between 1994 - 2016. Patients were grouped and analyzed according to culture results: 1) Staphylococcus aureus, 2) Streptococcus species (sp.), 3) Salmonella sp., 4) Enterococcus sp., 5) Gram-negative intestinal bacteria, 6) Other sp. (all other species found in culture), and 7) Negative cultures. Results: A sum of 182 patients were included, mean age 71 years (standard deviation; SD: 8.9). The median follow-up was 50.3 months (range 0 - 360). 128 (70.3%) patients had positive blood and/or tissue culture; Staphylococcus aureus n = 38 (20.9%), Streptococcus sp. n = 37 (20.3%), Salmonella sp. n = 19 (10.4%), Enterococcus sp. n = 16 (8.8%), Gram-negative intestinal bacteria n = 6, (3.3%), Other sp. n = 12 (6.6%) and Negative cultures n = 54 (29.7%). The estimated survival for the largest groups at 2-years after surgery was: Staphylococcus aureus 62% (95% Confidence interval 53.9 - 70.1), Streptococcus sp. 74.7% (67.4 - 82.0), Salmonella sp. 73.7% (63.6 - 83.8), Enterococcus sp. 61.9% (49.6 - 74.2), and Negative cultures 89.8% (85.5 - 94.1), P =.051. There were 37 IRCs (20.3%), and 19 (51.4%) were fatal, the frequency was insignificant between the groups. The majority of IRCs, 30/37 (81%), developed during the first postoperative year. Conclusion: In this assessment of microbiological findings of INAAs in Sweden, 50% of the pathogens were Staphylococcus aureus, Streptococcus sp., or Salmonella sp.. The overall 20%-frequency of IRCs, and its association with high mortality, motivates long-term antibiotic treatment regardless of microbial findings.
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| 47. |
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| 48. |
- Zheng, Weili, et al.
(författare)
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Cryo-Em Structure of Type 1 Pilus
- 2018
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Ingår i: Biophysical Journal. - : Biophysical Society. - 0006-3495 .- 1542-0086. ; 114:3, s. 370a-370a
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Urinary tract infections (UTIs) are caused by a wide range of pathogens, but the most common causative agent of UTIs is uropathogenic Escherichia coli (UPEC). Virtually all uropathogenic strains of E. coli encode filamentous surface adhesive organelles called type 1 pili, which are a subset of Chaperone-usher pathway (CUP) pili. CUP pili are also ubiquitously expressed on the surface of many other Gram-negative bacterial pathogens. They are important virulence factors facilitating host-pathogen interactions that are crucial for the establishment and persistence of an infection, and involved in regulating other key processes such as biofilm formation. We have solved the 4.2 Å resolution cryo-EM structure of the type 1 pilus, which was present as a background contaminant in a prep of type 4 pili. We have taken advantage of the strength of cryo-EM to separate different molecules and conformations present in solution to show that filament images which might otherwise have been discarded as a contaminant can actually be used to build an atomic model. The model reveals the residues that allow a long chain of FimA subunits, linked by the insertion of a β-strand of one subunit into the β-sheet of an adjacent subunit, to coil into a rigid rod. We show that site-specific mutation of these residues reduces the force needed to unwind the rod. Strikingly, one mutation (A22R) which showed the greatest reduction in unwinding force, eliminated bladder infections in a mouse model. This is presumably due to the fact that the altered mechanics of the A22R pilus rod cannot withstand the shear forces due to urinary flow in the bladder and bacteria harboring this mutation are cleared from the bladder. This provides new insights into the important role of pili mechanics in bacterial pathogenesis.
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| 49. |
- Zou, Zongsen, et al.
(författare)
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Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection
- 2024
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:31
-
Tidskriftsartikel (refereegranskat)abstract
- We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.
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| 50. |
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