| 1. |
- Ammanath, Aparna Viswanathan, et al.
(författare)
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Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53.
- 2024
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Ingår i: International Journal of Molecular Sciences. - 1422-0067. ; 25:15
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Tidskriftsartikel (refereegranskat)abstract
- Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John's wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of -7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.
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| 2. |
- Ammanath, Aparna Viswanathan, et al.
(författare)
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From an Hsp90 - binding protein to a peptide drug.
- 2022
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Ingår i: microLife. - : Oxford University Press (OUP). - 2633-6693. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and thereby increasing S. aureus internalization. The model Lpl protein, Lpl1 was shown to interact with the human heat shock proteins Hsp90α and Hsp90ß, suggesting that this interaction may trigger all observed activities. Here we synthesized Lpl1-derived peptides of different lengths and identified two overlapping peptides, namely, L13 and L15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreased F-actin levels and S. aureus internalization in epithelial cells but they also decreased phagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor, geldanamycin, showed a similar effect. The peptides not only interacted directly with Hsp90α, but also with the mother protein Lpl1. While L15 and L13 significantly decreased lethality of S. aureus bacteremia in an insect model, geldanamycin did not. In a mouse bacteremia model L15 was found to significantly decreased weight loss and lethality. Although the molecular bases of the L15 effect is still elusive, in vitro data indicate that simultaneous treatment of host immune cells with L15 or L13 and S. aureus significantly increase IL-6 production. L15 and L13 represent not antibiotics but they cause a significant reduction in virulence of multidrug-resistant S. aureus strains in in vivo models. In this capacity, they can be an important drug alone or additive with other agents.
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| 3. |
- Baranwal, Gaurav, et al.
(författare)
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Impact of cell wall peptidoglycan O-acetylation on the pathogenesis of Staphylococcus aureus in septic arthritis.
- 2017
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Ingår i: International journal of medical microbiology : IJMM. - : Elsevier BV. - 1618-0607 .- 1438-4221. ; 307:7, s. 388-397
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus (S. aureus) is one of the most common pathogen causing septic arthritis. To colonize the joints and establish septic arthritis this bacterium needs to resist the host innate immune responses. Lysozyme secreted by neutrophils and macrophages is an important defense protein present in the joint synovial fluids. S. aureus is known to be resistant to lysozyme due to its peptidoglycan modification by O-acetylation of N-acetyl muramic acid. In this study we have investigated the role of O-acetylated peptidoglycan in septic arthritis. Using mouse models for both local and hematogenous S. aureus arthritis we compared the onset and progress of the disease induced by O-acetyl transferase mutant and the parenteral wild type SA113 strain. The disease progression was assessed by observing the clinical parameters including body weight, arthritis, and functionality of the affected limbs. Further X-ray and histopathological examinations were performed to monitor the synovitis and bone damage. In local S. aureus arthritis model, mice inoculated with the ΔoatA strain developed milder disease (in terms of knee swelling, motor and movement functionality) compared to mice inoculated with the wild type SA113 strain. X-ray and histopathological data revealed that ΔoatA infected mice knee joints had significantly lesser joint destruction, which was accompanied by reduced bacterial load in knee joints. Similarly, in hematogenous S. aureus arthritis model, ΔoatA mutant strain induced significantly less severe clinical septic arthritis compared to its parental strain, which is in accordance with radiological findings. Our data indicate that peptidoglycan O-acetylation plays an important role in S. aureus mediated septic arthritis.
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| 4. |
- Hensel, Lukas, et al.
(författare)
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Global Behaviors, Perceptions, and the Emergence of Social Norms at the Onset of the COVID-19 Pandemic
- 2022
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Ingår i: Journal of Economic Behavior and Organization. - : Elsevier BV. - 0167-2681 .- 1879-1751. ; 193, s. 473-496
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a large-scale survey covering 58 countries and over 100,000 respondents between late March and early April 2020 to study beliefs and attitudes towards citizens’ and governments’ responses at the onset of the COVID-19 pandemic. Most respondents reported holding normative beliefs in support of COVID-19 containment measures, as well as high rates of adherence to these measures. They also believed that their government and their country’s citizens were not doing enough and underestimated the degree to which others in their country supported strong behavioral and policy responses to the pandemic. Normative beliefs were strongly associated with adherence, as well as beliefs about others’ and the government’s response. Lockdowns were associated with greater optimism about others’ and the government’s response, and improvements in measures of perceived mental well-being; these effects tended to be larger for those with stronger normative beliefs. Our findings highlight how social norms can arise quickly and effectively to support cooperation at a global scale.
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| 5. |
- Hu, Zhicheng, et al.
(författare)
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Phenol-soluble modulin α and β display divergent roles in mice with staphylococcal septic arthritis.
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMβ which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmβ). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMβ has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMβ strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMβ play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMβ protects arthritis development.
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| 6. |
- Löfblom, John, et al.
(författare)
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Staphylococcus carnosus : from starter culture to protein engineering platform
- 2017
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Ingår i: Applied Microbiology and Biotechnology. - : Springer. - 0175-7598 .- 1432-0614. ; 101:23-24, s. 8293-8307
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Forskningsöversikt (refereegranskat)abstract
- Since the 1950s, Staphylococcus carnosus is used as a starter culture for sausage fermentation where it contributes to food safety, flavor, and a controlled fermentation process. The long experience with S. carnosus has shown that it is a harmless and "food grade" species. This was confirmed by the genome sequence of S. carnosus TM300 that lacks genes involved in pathogenicity. Since the development of a cloning system in TM300, numerous genes have been cloned, expressed, and characterized and in particular, virulence genes that could be functionally validated in this non-pathogenic strain. A secretion system was developed for production and secretion of industrially important proteins and later modified to also enable display of heterologous proteins on the surface. The display system has been employed for various purposes, such as development of live bacterial delivery vehicles as well as microbial biocatalysts or bioadsorbents for potential environmental or biosensor applications. Recently, this surface display system has been utilized for display of peptide and protein libraries for profiling of protease substrates and for generation of various affinity proteins, e.g., Affibody molecules and scFv antibodies. In addition, by display of fragmented antigen-encoding genes, the surface expression system has been successfully used for epitope mapping of antibodies. Reviews on specific applications of S. carnosus have been published earlier, but here we provide a more extensive overview, covering a broad range of areas from food fermentation to sophisticated methods for protein-based drug discovery, which are all based on S. carnosus.
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| 7. |
- Mohammad, Majd, et al.
(författare)
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Staphylococcus aureus lipoproteins in infectious diseases.
- 2022
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Ingår i: Frontiers in microbiology. - : Frontiers Media SA. - 1664-302X. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Infections with the Gram-positive bacterial pathogen Staphylococcus aureus remain a major challenge for the healthcare system and demand new treatment options. The increasing antibiotic resistance of S. aureus poses additional challenges, consequently inflicting a huge strain in the society due to enormous healthcare costs. S. aureus expresses multiple molecules, including bacterial lipoproteins (Lpps), which play a role not only in immune response but also in disease pathogenesis. S. aureus Lpps, the predominant ligands of TLR2, are important for bacterial survival as they maintain the metabolic activity of the bacteria. Moreover, Lpps possess many diverse properties that are of vital importance for the bacteria. They also contribute to host cell invasion but so far their role in different staphylococcal infections has not been fully defined. In this review, we summarize the current knowledge about S. aureus Lpps and their distinct roles in various infectious disease animal models, such as septic arthritis, sepsis, and skin and soft tissue infections. The molecular and cellular response of the host to S. aureus Lpp exposure is also a primary focus.
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| 8. |
- Mohammad, Majd, et al.
(författare)
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Staphylococcus aureus lipoproteins promote abscess formation in mice, shielding bacteria from immune killing.
- 2021
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite being a major bacterial factor in alerting the human immune system, the role of Staphylococcus aureus (S. aureus) lipoproteins (Lpp) in skin infections remains largely unknown. Here, we demonstrated that subcutaneous injection of S. aureus Lpp led to infiltration of neutrophils and monocytes/macrophages and induced skin lesions in mice. Lipid-moiety of S. aureus Lpp and host TLR2 was responsible for such effect. Lpp-deficient S. aureus strains exhibited smaller lesion size and reduced bacterial loads than their parental strains; the altered phenotype in bacterial loads was TLR2-independent. Lpp expression in skin infections contributed to imbalanced local hemostasis toward hypercoagulable state. Depletion of leukocytes or fibrinogen abrogated the effects induced by Lpp in terms of skin lesions and bacterial burden. Our data suggest that S. aureus Lpp induce skin inflammation and promote abscess formation that protects bacteria from innate immune killing. This suggests an intriguing bacterial immune evasion mechanism.
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| 9. |
- Mohammad, Majd, et al.
(författare)
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The role of Staphylococcus aureus lipoproteins in hematogenous septic arthritis.
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Permanent joint dysfunction is a devastating complication in patients with septic arthritis. Staphylococcus aureus (S. aureus) lipoproteins (Lpp), the predominant ligands for TLR2, are known to be arthritogenic and induce bone destruction when introduced directly into the joint. Here, we aim to investigate the importance of S. aureus Lpp and TLR2 in a hematogenous septic arthritis model, which is the most common route of infection in humans. C57BL/6 wild-type and TLR2 deficient mice were intravenously inoculated with S. aureus Newman parental strain or its lipoprotein-deficient Δlgt mutant strain. The clinical course of septic arthritis, radiological changes, and serum levels of cytokines and chemokines, were assessed. Newman strain induced more severe and frequent clinical septic polyarthritis compared to its Δlgt mutant in TLR2 deficient mice, but not in wild-type controls. Bone destruction, however, did not differ between groups. Lpp expression was associated with higher mortality, weight loss as well as impaired bacterial clearance in mouse kidneys independent of TLR2. Furthermore, Lpp expression induced increased systemic pro-inflammatory cytokine and neutrophil chemokine release. Staphylococcal Lpp are potent virulence factors in S. aureus systemic infection independent of host TLR2 signalling. However, they have a limited impact on bone erosion in hematogenous staphylococcal septic arthritis.
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| 10. |
- Mohammad, Majd, et al.
(författare)
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The YIN and YANG of lipoproteins in developing and preventing infectious arthritis by Staphylococcus aureus.
- 2019
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Rapid bone destruction often leads to permanent joint dysfunction in patients with septic arthritis, which is mainly caused by Staphylococcus aureus (S. aureus). Staphylococcal cell wall components are known to induce joint inflammation and bone destruction. Here, we show that a single intra-articular injection of S. aureus lipoproteins (Lpps) into mouse knee joints induced chronic destructive macroscopic arthritis through TLR2. Arthritis was characterized by rapid infiltration of neutrophils and monocytes. The arthritogenic effect was mediated mainly by macrophages/monocytes and partially via TNF-α but not by neutrophils. Surprisingly, a S. aureus mutant lacking Lpp diacylglyceryl transferase (lgt) caused more severe joint inflammation, which coincided with higher bacterial loads of the lgt mutant in local joints than those of its parental strain. Coinjection of pathogenic S. aureus LS-1 with staphylococcal Lpps into mouse knee joints caused improved bacterial elimination and diminished bone erosion. The protective effect of the Lpps was mediated by their lipid moiety and was fully dependent on TLR2 and neutrophils. The blocking of CXCR2 on neutrophils resulted in total abrogation of the protective effect of the Lpps. Our data demonstrate that S. aureus Lpps elicit innate immune responses, resulting in a double-edged effect. On the one hand, staphylococcal Lpps boost septic arthritis. On the other hand, Lpps act as adjuvants and activate innate immunity, which could be useful for combating infections with multiple drug-resistant strains.
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