MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections

One of the most pressing challenges of our era is the rising occurrence of bacteria that are resistant to antibiotics. Staphylococci are prominent pathogens in humans, which have developed multiple strategies to evade the effects of antibiotics. Infections caused by these bacteria have resulted in a high burden on the health care system and a significant loss of lives. In this study, we have successfully engineered lytic enzymes that exhibit an extraordinary ability to eradicate staphylococci. Our findings substantiate the importance of meticulous lead candidate selection to identify therapeutically promising peptidoglycan hydrolases with unprecedented activity. Hence, they offer a promising new avenue for treating staphylococcal infections

Shiga Toxin Is Transported into the Nucleoli of Intestinal Epithelial Cells via a Carrier-Dependent Process

Shiga toxin (Stx) produced by the invasive Shigella dysenteriae serotype 1 (S. dysenteriae1) causes gastrointestinal and kidney complications. It has been assumed that Stx is released intracellularly after enterocyte invasion by S. dysenteriae1. However, there is little information about Stx distribution inside S. dysenteriae1-infected enterocytes. Here, we use intestinal epithelial T84 cells to characterize the trafficking of Stx delivered into the cytosol, in ways that mimic aspects of S. dysenteriae1 infection. We find that cytoplasmic Stx is transported into nucleoli. Stx nucleolar movement is carrier- and energy-dependent. Stx binding to the nucleoli of normal human enterocytes in vitro supports possible roles for nucleolar trafficking in toxin-induced intestinal pathology

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Measurement-based harmonic current modeling of mobile storage for power quality study in the distribution system

Electric vehicles (EVs) can be utilized as mobile storages in a power system. The use of battery chargers can cause current harmonics in the supplied AC system. In order to analyze the impact of different EVs with regard to their number and their emission of current harmonics, a generic harmonic current model of EV types was built and implemented in the power system simulation tool PSS®NETOMAC. Based on the measurement data for different types of EVs three standardized harmonic EV models were developed and parametrized. Further, the identified harmonic models are used by the computation of load flow in a modeled, German power distribution system. As a benchmark, a case scenario was studied regarding a high market penetration of EVs in the year 2030 for Germany. The impact of the EV charging on the power distribution system was analyzed and evaluated with valid power quality standards

Measurement-based harmonic current modeling of mobile storage for power quality study in the distribution system

Electric vehicles (EVs) can be utilized as mobile storages in a power system. The use of battery chargers can cause current harmonics in the supplied AC system. In order to analyze the impact of different EVs with regardto their number and their emission of current harmonics, a generic harmonic current model of EV types was built and implemented in the power system simulation tool PSS®NETOMAC. Based on the measurement data for different types of EVs three standardized harmonic EV models were developed and parametrized. Further, the identified harmonic models are used by the computation of load flow in a modeled, German power distribution system. As a benchmark, a case scenario was studied regarding a high market penetration of EVs in the year 2030 for Germany. The impact of the EV charging on the power distribution system was analyzed and evaluated with valid power quality standards

Motivation and Diabetes: Time for a Paradigm Shift? - A Position Paper -

Non-adherence to treatment recommendations for patients with diabetes is widespread. This applies to medication as well as recommendations for a healthy lifestyle with appropriate physical activity, a healthy diet, and, if necessary, an end to smoking and weight control. Disregard of these recommendations has been shown to increase the risk of diabetes complications, morbidity and premature mortality. Physicians ' responses to this patient behavior include increased efforts to improve adherence to therapy and often result in a feeling of resignation in the long term. Research efforts focus on an increasing number of interventions to improve therapy adherence, with the results of meta-analyses indicating only moderate success. This position paper presents a practice-oriented approach for discussion that aims to improve the problems described. We reflect on the different roles and responsibilities of patients on the one hand and physicians and other professional groups (diabetes counsellors, nurses, and psychotherapists) on the other. A new classification of different types of non-adherence to therapy is proposed. These constitute the starting point for a practice-related algorithm for the medical handling of the different types of non-adherence, in which the roles and responsibilities of practitioners and patients are explicitly clarified. Thereby no adherence to therapy of patients is pushed. Rather, the aim is for patients to make an informed and responsible decision for or against a doctor's suggestion and for this to be accepted by the physician so that frustrations on both sides are avoided. Finally, theses regarding motivation problems in diabetes will be presented for discussion

MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections

ABSTRACTBacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin-resistant Staphylococcus aureus is one of the deadliest pathogens and a high-priority pathogen according to the World Health Organization. Peptidoglycan hydrolases (PGHs) of phage origin have been postulated as a new class of antimicrobials for the treatment of bacterial infections, with a novel mechanism of action and no known resistances. The modular architecture of PGHs permits the creation of chimeric PGH libraries. In this study, the chimeric enzyme MEndoB was selected from a library of staphylococcal PGHs based on its rapid and sustained activity against staphylococci in human serum. The benefit of the presented screening approach was illustrated by the superiority of MEndoB in a head-to-head comparison with other PGHs intended for use against staphylococcal bacteremia. MEndoB displayed synergy with antibiotics and rapid killing in human whole blood with complete inhibition of re-growth over 24 h at low doses. Successful treatment of S. aureus-infected zebrafish larvae with MEndoB provided evidence for its in vivo effectiveness. This was further confirmed in a lethal systemic mouse infection model in which MEndoB significantly reduced S. aureus loads and tumor necrosis factor alpha levels in blood in a dose-dependent manner, which led to increased survival of the animals. Thus, the thorough lead candidate selection of MEndoB resulted in an outstanding second-generation PGH with in vitro, ex vivo, and in vivo results supporting further development.IMPORTANCEOne of the most pressing challenges of our era is the rising occurrence of bacteria that are resistant to antibiotics. Staphylococci are prominent pathogens in humans, which have developed multiple strategies to evade the effects of antibiotics. Infections caused by these bacteria have resulted in a high burden on the health care system and a significant loss of lives. In this study, we have successfully engineered lytic enzymes that exhibit an extraordinary ability to eradicate staphylococci. Our findings substantiate the importance of meticulous lead candidate selection to identify therapeutically promising peptidoglycan hydrolases with unprecedented activity. Hence, they offer a promising new avenue for treating staphylococcal infections

Linker-Improved Chimeric Endolysin Selectively Kills Staphylococcus aureus In Vitro, on Reconstituted Human Epidermis, and in a Murine Model of Skin Infection

Staphylococcus aureus causes a broad spectrum of diseases in humans and animals. It is frequently associated with inflammatory skin disorders such as atopic dermatitis, where it aggravates symptoms. Treatment of S. aureus-associated skin infections with antibiotics is discouraged due to their broad-range deleterious effect on healthy skin microbiota and their ability to promote the development of resistance. Thus, novel S. aureus-specific antibacterial agents are desirable. We constructed two chimeric cell wall-lytic enzymes, Staphefekt SA.100 and XZ.700, which are composed of functional domains from the bacteriophage endolysin Ply2638 and the bacteriocin lysostaphin. Both enzymes specifically killed S. aureus and were inactive against commensal skin bacteria such as Staphylococcus epidermidis, with XZ.700 proving more active than SA.100 in multiple in vitro activity assays. When surface-attached mixed staphylococcal cultures were exposed to XZ.700 in a simplified microbiome model, the enzyme selectively removed S. aureus and retained S. epidermidis. Furthermore, XZ.700 did not induce resistance in S. aureus during repeated rounds of exposure to sublethal concentrations. Finally, we demonstrated that XZ.700 formulated as a cream is effective at killing S. aureus on reconstituted human epidermis and that an XZ.700-containing gel significantly reduces bacterial numbers compared to an untreated control in a mouse model of S. aureus-induced skin infection.ISSN:0066-4804ISSN:1098-659