The battle against antimicrobial resistant bacterial infections: next stage development of antimicrobial peptides

Bacterial infections are becoming harder-to-treat with current antibiotics, due to antimicrobial resistance and biofilm-formation. Therefore, there is an urgent need for novel antibacterial agents and antimicrobial peptides (AMPs) may fulfill this role. Herein, three strategies were explored for optimization of our lead AMP SAAP-148 to combat bacterial infections: i) chemical lead-optimization, ii) combination therapy with other antimicrobial agents and iii) innovative AMP delivery systems. The latter strategy was also applied to another promising AMP, the snake cathelicidin Ab-Cath. First, we demonstrated that conjugation of short polyethylene glycol chains to SAAP-148 reduced the peptide’s cytotoxicity and remarkably improved its ability to modulate the immune system to a more pro-inflammatory subset. Second, it was shown that combinations of SAAP-148 and novel antibiotic halicin were more effective than single agent treatment against planktonic bacteria of specific resistant bacterial strains, also in clinically relevant cell models. Third, we demonstrated that hyaluronic acid-based nanogels allow for efficient encapsulation of SAAP-148 and Ab-Cath, thereby improving the selectivity index of both peptides by maintaining antimicrobial activities against resistant bacteria and reducing cytotoxic activities against mammalian cells. Thus, the findings described in this thesis contribute to the development of SAAP-148 and Ab-Cath as therapeutics to combat bacterial infections.The work presented in this thesis was financially supported by the Dutch Research Council (NWO), Novel Antibacterial Compounds and Therapies Antagonizing Resistance Program: grant number 16434.LUMC / Geneeskund

Current advances in lipid and polymeric antimicrobial peptide delivery systems and coatings for the prevention and treatment of bacterial infections

Bacterial infections constitute a threat to public health as antibiotics are becoming less effective due to the emergence of antimicrobial resistant strains and biofilm and persister formation. Antimicrobial peptides (AMPs) are considered excellent alternatives to antibiotics; however, they suffer from limitations related to their peptidic nature and possible toxicity. The present review critically evaluates the chemical characteristics and antibacterial effects of lipid and polymeric AMP delivery systems and coatings that offer the promise of enhancing the efficacy of AMPs, reducing their limitations and prolonging their half-life. Unfortunately, the antibacterial activities of these systems and coatings have mainly been evaluated in vitro against planktonic bacteria in less biologically relevant conditions, with only some studies focusing on the antibiofilm activities of the formulated AMPs and on the antibacterial effects in animal models. Further improvements of lipid and polymeric AMP delivery systems and coatings may involve the functionalization of these systems to better target the infections and an analysis of the antibacterial activities in biologically relevant environments. Based on the available data we proposed which polymeric AMP delivery system or coatings could be profitable for the treatment of the different hard-to-treat infections, such as bloodstream infections and catheter- or implant-related infections.Immunogenetics and cellular immunology of bacterial infectious disease

Intercomparison of Metop-A SO2 measurements during the 2010- 2011 Icelandic eruptions

The European Space Agency project Satellite Monitoring of Ash and Sulphur Dioxide for the mitigation of Aviation Hazards, was introduced after the eruption of the Icelandic volcano Eyjafjallajökull in the spring of 2010 to facilitate the development of an optimal EndtoEnd System for Volcanic Ash Plume Monitoring and Prediction. The Eyjafjallajökull plume drifted towards Europe and caused major disruptions of European air traffic for several weeks affecting the everyday life of millions of people. The limitations in volcanic plume monitoring and prediction capabilities gave birth to this observational system which is based on comprehensive satellitederived ash plume and sulphur dioxide [SO2] level estimates, as well as a widespread validation using supplementary satellite, aircraft and groundbased measurements. Intercomparison of the volcanic total SO2 column and plume height observed by GOME2/ MetopA and IASI/MetopA are shown before, during and after the Eyjafjallajökull 2010 eruptions as well as for the 2011 Grímsvötn eruption. Colocated groundbased Brewer Spectrophotometer data extracted from the World Ozone and Ultraviolet Radiation Data Centre for de Bilt, the Netherlands, are also compared to the different satellite estimates. Promising agreement is found for the two different types of instrument for the SO2 columns with linear regression coefficients ranging around from 0.64 when comparing the different instruments and 0.85 when comparing the two different IASI algorithms. The agreement for the plume height is lower, possibly due to the major differences between the height retrieval part of the GOME2 and IASI algorithms. The comparisons with the Brewer groundbased station in de Bilt, The Netherlands show good qualitative agreement for the peak of the event however stronger eruptive signals are required for a longer quantitative comparison

Uptake and subcellular distribution of radiolabeled polymersomes for radiotherapy

Polymersomes have the potential to be applied in targeted alpha radionuclide therapy, while in addition preventing release of recoiling daughter isotopes. In this study, we investigated the cellular uptake, post uptake processing and intracellular localization of polymersomes. Methods: High-content microscopy was used to validate polymersome uptake kinetics. Confocal (live cell) microscopy was used to elucidate the uptake mechanism and DNA damage induction. Intracellular distribution of polymersomes in 3-D was determined using super-resolution microscopy. Results: We found that altering polymersome size and concentration affects the initial uptake and overall uptake capacity; uptake efficiency and eventual plateau levels varied between cell lines;

A randomised comparison of the effect of haemodynamic monitoring with CardioMEMS in addition to standard care on quality of life and hospitalisations in patients with chronic heart failure: Design and rationale of the MONITOR HF multicentre randomised clinical trial

Background: Assessing haemodynamic congestion based on filling pressures instead of clinical congestion can be a way to further improve quality of life (QoL) and clinical outcome by intervening before symptoms or weight gain occur in heart failure (HF) patients. The clinical efficacy of remote monitoring of pulmonary artery (PA) pressures (CardioMEMS; Abbott Inc., Atlanta, GA, USA) has been demonstrated in the USA. Currently, the PA sensor is not reimbursed in the European Union as its benefit when applied in addition to standard HF care is unknown in Western European countries, including the Netherlands. Aims: To demonstrate the efficacy and cost-effectiveness of haemodynamic PA monitoring in addition to contemporary standard HF care in a high-quality Western European health care system. Methods: The current study is a prospective, multi-centre, randomised clinical trial in 340 patients with chronic HF (New York Heart Association functional class III) randomised to HF care including remote monitoring with the CardioMEMS PA sensor or standard HF care alone. Eligible patients have at least one hospitalisation for HF in 12 months before enrolment and will be randomised in a 1:1 ratio. Minimum follow-up will be 1 year. The primary endpoint is the change in QoL as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Secondary endpoints are the number of HF hospital admissions and changes in health status assessed by EQ-5D-5L questionnaire including healt

The battle against antimicrobial resistant bacterial infections: next stage development of antimicrobial peptides

Bacterial infections are becoming harder-to-treat with current antibiotics, due to antimicrobial resistance and biofilm-formation. Therefore, there is an urgent need for novel antibacterial agents and antimicrobial peptides (AMPs) may fulfill this role. Herein, three strategies were explored for optimization of our lead AMP SAAP-148 to combat bacterial infections: i) chemical lead-optimization, ii) combination therapy with other antimicrobial agents and iii) innovative AMP delivery systems. The latter strategy was also applied to another promising AMP, the snake cathelicidin Ab-Cath. First, we demonstrated that conjugation of short polyethylene glycol chains to SAAP-148 reduced the peptide’s cytotoxicity and remarkably improved its ability to modulate the immune system to a more pro-inflammatory subset. Second, it was shown that combinations of SAAP-148 and novel antibiotic halicin were more effective than single agent treatment against planktonic bacteria of specific resistant bacterial strains, also in clinically relevant cell models. Third, we demonstrated that hyaluronic acid-based nanogels allow for efficient encapsulation of SAAP-148 and Ab-Cath, thereby improving the selectivity index of both peptides by maintaining antimicrobial activities against resistant bacteria and reducing cytotoxic activities against mammalian cells. Thus, the findings described in this thesis contribute to the development of SAAP-148 and Ab-Cath as therapeutics to combat bacterial infections.</p

The battle against antimicrobial resistant bacterial infections: next stage development of antimicrobial peptides

Bacterial infections are becoming harder-to-treat with current antibiotics, due to antimicrobial resistance and biofilm-formation. Therefore, there is an urgent need for novel antibacterial agents and antimicrobial peptides (AMPs) may fulfill this role. Herein, three strategies were explored for optimization of our lead AMP SAAP-148 to combat bacterial infections: i) chemical lead-optimization, ii) combination therapy with other antimicrobial agents and iii) innovative AMP delivery systems. The latter strategy was also applied to another promising AMP, the snake cathelicidin Ab-Cath. First, we demonstrated that conjugation of short polyethylene glycol chains to SAAP-148 reduced the peptide’s cytotoxicity and remarkably improved its ability to modulate the immune system to a more pro-inflammatory subset. Second, it was shown that combinations of SAAP-148 and novel antibiotic halicin were more effective than single agent treatment against planktonic bacteria of specific resistant bacterial strains, also in clinically relevant cell models. Third, we demonstrated that hyaluronic acid-based nanogels allow for efficient encapsulation of SAAP-148 and Ab-Cath, thereby improving the selectivity index of both peptides by maintaining antimicrobial activities against resistant bacteria and reducing cytotoxic activities against mammalian cells. Thus, the findings described in this thesis contribute to the development of SAAP-148 and Ab-Cath as therapeutics to combat bacterial infections.</p

Immune Evasion by Epstein-Barr Virus

Therapeutic cell differentiatio

Silencing the shutoff protein of Epstein-Barr virus in productively infected B cells points to (innate) targets for immune evasion

Therapeutic cell differentiatio

Intercomparison of Metop-A SO2 measurements during the 2010- 2011 Icelandic eruptions

The European Space Agency project Satellite Monitoring of Ash and Sulphur Dioxide for the mitigation of Aviation Hazards, was introduced after the eruption of the Icelandic volcano Eyjafjallajökull in the spring of 2010 to facilitate the development of an optimal EndtoEnd System for Volcanic Ash Plume Monitoring and Prediction. The Eyjafjallajökull plume drifted towards Europe and caused major disruptions of European air traffic for several weeks affecting the everyday life of millions of people. The limitations in volcanic plume monitoring and prediction capabilities gave birth to this observational system which is based on comprehensive satellitederived ash plume and sulphur dioxide [SO2] level estimates, as well as a widespread validation using supplementary satellite, aircraft and groundbased measurements. Intercomparison of the volcanic total SO2 column and plume height observed by GOME2/ MetopA and IASI/MetopA are shown before, during and after the Eyjafjallajökull 2010 eruptions as well as for the 2011 Grímsvötn eruption. Colocated groundbased Brewer Spectrophotometer data extracted from the World Ozone and Ultraviolet Radiation Data Centre for de Bilt, the Netherlands, are also compared to the different satellite estimates. Promising agreement is found for the two different types of instrument for the SO2 columns with linear regression coefficients ranging around from 0.64 when comparing the different instruments and 0.85 when comparing the two different IASI algorithms. The agreement for the plume height is lower, possibly due to the major differences between the height retrieval part of the GOME2 and IASI algorithms. The comparisons with the Brewer groundbased station in de Bilt, The Netherlands show good qualitative agreement for the peak of the event however stronger eruptive signals are required for a longer quantitative comparison.Published5IT. Osservazioni satellitariJCR Journalope