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•A 4-antigen S. aureus vaccine (SA4Ag) targeting multiple virulence factors.•A Phase 1 study after finalizing manufacturing process prior to an efficacy study.•SA4Ag was well tolerated with a satisfactory safety profile in adults 18–<65years.•SA4Ag rapidly induced high level bacteria-killing antibodies in adults 18–<65years.•The postoperative protective effect of SA4Ag is being assessed in a Phase 2b trial. Staphylococcus aureus is a leading cause of healthcare-associated infections. No preventive vaccine is currently licensed. SA4Ag is an investigational 4-antigen S. aureus vaccine, composed of capsular polysaccharide conjugates of serotypes 5 and 8 (CP5 and CP8), recombinant surface protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (rMntC). This Phase 1 study aimed to confirm the safety and immunogenicity of SA4Ag produced by the final manufacturing process before efficacy study initiation in a surgical population. Healthy adults (18–<65years) received one intramuscular SA4Ag injection. Serum functional antibodies were measured at baseline and Day 29 post-vaccination. An opsonophagocytic activity (OPA) assay measured the ability of vaccine-induced antibodies to CP5 and CP8 to kill S. aureus clinical isolates. For MntC and ClfA, antigen-specific immunogenicity was assessed via competitive Luminex® immunoassay (cLIA) and via fibrinogen-binding inhibition (FBI) assay for ClfA only. Reactogenicity and adverse event data were collected. One hundred participants were vaccinated. SA4Ag was well tolerated, with a satisfactory safety profile. On Day 29, OPA geometric mean titers (GMTs) were 45,738 (CP5, 95% CI: 38,078–54,940) and 42,652 (CP8, 95% CI: 32,792–55,477), consistent with 69.2- and 28.9-fold rises in bacteria-killing antibodies, respectively; cLIA GMTs were 2064.4 (MntC, 95% CI: 1518.2–2807.0) and 3081.4 (ClfA, 95% CI: 2422.2–3920.0), consistent with 19.6- and 12.3-fold rises, respectively. Similar to cLIA results, ClfA FBI titers rose 11.0-fold (GMT: 672.2, 95% CI: 499.8–904.2). The vast majority of participants achieved the pre-defined biologically relevant thresholds: CP5: 100%; CP8: 97.9%, ClfA: 87.8%; and MntC 96.9%. SA4Ag was safe, well tolerated, and rapidly induced high levels of bacteria-killing antibodies in healthy adults. A Phase 2B efficacy trial in adults (18–85years) undergoing elective spinal fusion is ongoing to assess SA4Ag’s ability to prevent postoperative invasive surgical site and bloodstream infections caused by S. aureus. Clinicaltrials.gov Identifier: NCT02364596.

Background Topical steroids prepared as oral viscous slurries have become common in the treatment of eosinophilic esophagitis. Esophageal mucosal contact time correlates with clinical and histologic improvement. Aim To compare the mucosal contact time of alternative oral viscous budesonide (OVB) slurries with the conventional sucralose OVB. Methods A blinded randomized crossover trial investigating esophageal clearance of three OVB slurry preparations was done on healthy adults. Honey and xanthan gum OVB slurries were compared with standard sucralose OVB in 24 randomly assigned subjects. Each subject ingested the sucralose OVB and either the honey or xanthan gum OVB slurries. The esophageal clearance of each slurry was evaluated as an area under the curve (AUC) using 1 millicurie of technetium-99m-sulfur colloid (Tc99) co-administered in each OVB preparation using nuclear scintigraphy. A standardized taste survey was also administered. Results Xanthan gum had greater mucosal contact time compared to sucralose as measured by a higher AUC at 3 min ( P  = 0.002), while honey showed no significant difference in esophageal clearance relative to sucralose. Taste scores were significantly higher in the honey group, while scores for xanthan gum were no different from standard sucralose. Conclusion OVB slurries utilizing xanthan gum may be a superior alternative to a sucralose-based slurry due to its increased mucosal contact time and similar taste tolerance. Honey may be a suitable alternative as well, due to its similar contact time and favorable taste.

Background Several attempts to improve immune function in young children have been made and encouraging results have been collected with pidotimod (PDT), a synthetic dipeptide molecule that seems to have immunomodulatory activity on both innate and adaptive responses. Until now, the effects of PDT on the immune system have only been studied in vivo after long-term administration to evaluate whether its immunomodulatory activity might prevent the development of infections. This study was planned to evaluate the immunomodulatory activity of PDT administered together with standard antibiotic therapy in children hospitalized for community-acquired pneumonia (CAP). Methods A total of 20 children hospitalized for community-acquired pneumonia (CAP) were randomized at a 1:1 ratio to receive either standard antibiotics plus pidotimod (PDT) or standard antibiotics alone to evaluate the immunomodulatory activity of PDT. Blood samples for the evaluation of immunological parameters were drawn at the time of recruitment (T0) (i.e., before therapy administration), at T3 and T5 (i.e., 3 and 5 days after the initiation of therapy) as well as at T21 (i.e., 7 days after the therapy ended). Results Following pneumococcal polysaccharide stimulation, the percentage of dendritic cells (DCs) expressing activation and costimulatory molecules was significantly higher in children receiving PDT plus antibiotics than in the controls. A significant increase in tumor necrosis factor-α and/or interleukin-12 secretion and expression of toll like receptor 2 was observed in PDT-treated children compared with controls; this was followed by an increased release of proinflammatory cytokines by monocytes. In the PDT-treated group, mRNA expression of antimicrobial peptides and genes involved in the inflammatory response were also augmented in comparison with the controls. Conclusions These results demonstrate, for the first time, that PDT administered together with standard antibiotics is associated with a favorable persistent immunomodulatory effect in children with CAP.

The effect of consumption of PolyGlycopleX® (PGX®) was compared to wheat dextrin (WD) in combination with a standard meal, on postprandial satiety and glycaemia in a double-blind, randomised crossover trial, of 14 healthy subjects trained as a satiety panel. At each of six two-hour satiety sessions, subjects consumed one of three different test meals on two separate occasions. The test meals were: a standard meal plus 5 g PGX; a standard meal plus 4.5 g of PGX as softgels; and a standard meal plus 5 g of WD. Subjects recorded fullness using a labelled magnitude scale at 0, 15, 30, 45, 60, 90, and 120 min and the total area under the curve (AUC), mean fullness vs. time was calculated. The meals with PGX (in granular and softgel form) gave higher satiety (AUC) (477 ± 121 and 454 ± 242 cm·min), than the meal with WD (215 ± 261 cm·min) (p < 0.001). Subjects had blood glucose levels measured after the meals with PGX (granules) and WD. Glucose response (AUC) was significantly lower (p < 0.001) after the PGX meal than for the WD meal. The high viscosity reported for PGX is a likely mechanism behind the significant satiety and blood glucose modulating effects observed in this study.

A substantial and increasing number of human diseases are associated with changes in the gut microbiota, and discovering the molecules and mechanisms underlying these associations represents a major research goal. Multiple studies associate Ruminococcus gnavus, a prevalent gut microbe, with Crohn’s disease, a major type of inflammatory bowel disease. We have found that R. gnavus synthesizes and secretes a complex glucorhamnan polysaccharide with a rhamnose backbone and glucose sidechains. Chemical and spectroscopic studies indicated that the glucorhamnan was largely a repeating unit of five sugars with a linear backbone formed from three rhamnose units and a short sidechain composed of two glucose units. The rhamnose backbone is made from 1,2- and 1,3-linked rhamnose units, and the sidechain has a terminal glucose linked to a 1,6-glucose. This glucorhamnan potently induces inflammatory cytokine (TNFα) secretion by dendritic cells, and TNFα secretion is dependent on toll-like receptor 4 (TLR4). We also identify a putative biosynthetic gene cluster for this molecule, which has the four biosynthetic genes needed to convert glucose to rhamnose and the five glycosyl transferases needed to build the repeating pentasaccharide unit of the inflammatory glucorhamnan.

Exopolysaccharides and extracellular DNA are important structural components that contribute to the self-assembly of large aggregates or microcolonies that are characteristic of biofilms. Pseudomonas aeruginosa is capable of producing multiple exopolysaccharides, including alginate, Psl, and Pel. At present, little is known about Pel’s chemical structure and its role in microcolony formation. Our results demonstrate that Pel is composed of cationic amino sugars. Using this knowledge, we have developed a Pel-specific lectin stain to directly visualize Pel in biofilms. We show that the positive charge on Pel facilitates its binding to extracellular DNA in the biofilm stalk, and that Pel can compensate for lack of Psl in the biofilm periphery. Biofilm formation is a complex, ordered process. In the opportunistic pathogen Pseudomonas aeruginosa , Psl and Pel exopolysaccharides and extracellular DNA (eDNA) serve as structural components of the biofilm matrix. Despite intensive study, Pel’s chemical structure and spatial localization within mature biofilms remain unknown. Using specialized carbohydrate chemical analyses, we unexpectedly found that Pel is a positively charged exopolysaccharide composed of partially acetylated 1→4 glycosidic linkages of N -acetylgalactosamine and N -acetylglucosamine. Guided by the knowledge of Pel’s sugar composition, we developed a tool for the direct visualization of Pel in biofilms by combining Pel-specific Wisteria floribunda lectin staining with confocal microscopy. The results indicate that Pel cross-links eDNA in the biofilm stalk via ionic interactions. Our data demonstrate that the cationic charge of Pel is distinct from that of other known P. aeruginosa exopolysaccharides and is instrumental in its ability to interact with other key biofilm matrix components.

Bacterial biofilm infections account for a major proportion of chronic and medical device associated infections in humans, yet our ability to control them is compromised by their inherent tolerance to antimicrobial agents. Cold atmospheric plasma (CAP) represents a promising therapeutic option. CAP treatment of microbial biofilms represents the convergence of two complex phenomena: the production of a chemically diverse mixture of reactive species and intermediates, and their interaction with a heterogeneous 3D interface created by the biofilm extracellular polymeric matrix. Therefore, understanding these interactions and physiological responses to CAP exposure are central to effective management of infectious biofilms. We review the unique opportunities and challenges for translating CAP to the management of biofilms. Biofilms are implicated in around 65% of all chronic human infections, including those associated with indwelling medical devices such as catheters and prostheses. Biofilm infections are often asymptomatic between exacerbations and challenging to detect and effectively treat using conventional antibiotics and antimicrobial agents. CAP provides an effective multimodal, multitarget approach for controlling microbial biofilms. Biofilms express a complex extracellular matrix of polymeric substances that may attenuate the antimicrobial efficacy of CAP via interactions with CAP-generated RONS. Biofilm tolerance to CAP is variable between species and between strains of the same species, which may be due to production of EPS, RONS-detoxifying enzymes, or acquired tolerance to physiological RONS during chronic infections.

The polysaccharide capsule is essential for the pathogenicity of pneumococcus, which is responsible for millions of deaths worldwide each year. Currently available pneumococcal vaccines are designed to elicit antibodies to the capsule polysaccharides of the pneumococcal isolates commonly causing diseases, and the antibodies provide protection only against the pneumococcus expressing the vaccine-targeted capsules. Since pneumococci can produce different capsule polysaccharides and therefore reduce vaccine effectiveness, it is important to track the appearance of novel pneumococcal capsule types and how these new capsules are created. Herein, we describe a new and the 100th pneumococcal capsule type with unique chemical and serological properties. The capsule type was named 10D for its serologic similarity to 10A. Genetic studies provide strong evidence that pneumococcus created 10D capsule polysaccharide by capturing a large genetic fragment from an oral streptococcus. Such interspecies genetic exchanges could greatly increase diversity of pneumococcal capsules and complicate serotype shifts. Streptococcus pneumoniae (pneumococcus) is a major human pathogen producing structurally diverse capsular polysaccharides. Widespread use of highly successful pneumococcal conjugate vaccines (PCVs) targeting pneumococcal capsules has greatly reduced infections by the vaccine types but increased infections by nonvaccine serotypes. Herein, we report a new and the 100th capsule type, named serotype 10D, by determining its unique chemical structure and biosynthetic roles of all capsule synthesis locus ( cps ) genes. The name 10D reflects its serologic cross-reaction with serotype 10A and appearance of cross-opsonic antibodies in response to immunization with 10A polysaccharide in a 23-valent pneumococcal vaccine. Genetic analysis showed that 10D cps has three large regions syntenic to and highly homologous with cps loci from serotype 6C, serotype 39, and an oral streptococcus strain ( S. mitis SK145). The 10D cps region syntenic to SK145 is about 6 kb and has a short gene fragment of wciN α at the 5′ end. The presence of this nonfunctional wciN α fragment provides compelling evidence for a recent interspecies genetic transfer from oral streptococcus to pneumococcus. Since oral streptococci have a large repertoire of cps loci, widespread PCV usage could facilitate the appearance of novel serotypes through interspecies recombination. IMPORTANCE The polysaccharide capsule is essential for the pathogenicity of pneumococcus, which is responsible for millions of deaths worldwide each year. Currently available pneumococcal vaccines are designed to elicit antibodies to the capsule polysaccharides of the pneumococcal isolates commonly causing diseases, and the antibodies provide protection only against the pneumococcus expressing the vaccine-targeted capsules. Since pneumococci can produce different capsule polysaccharides and therefore reduce vaccine effectiveness, it is important to track the appearance of novel pneumococcal capsule types and how these new capsules are created. Herein, we describe a new and the 100th pneumococcal capsule type with unique chemical and serological properties. The capsule type was named 10D for its serologic similarity to 10A. Genetic studies provide strong evidence that pneumococcus created 10D capsule polysaccharide by capturing a large genetic fragment from an oral streptococcus. Such interspecies genetic exchanges could greatly increase diversity of pneumococcal capsules and complicate serotype shifts.

In the skin care field, bacterial nanocellulose (BNC), a versatile polysaccharide produced by non-pathogenic acetic acid bacteria, has received increased attention as a promising candidate to replace synthetic polymers (e.g., nylon, polyethylene, polyacrylamides) commonly used in cosmetics. The applicability of BNC in cosmetics has been mainly investigated as a carrier of active ingredients or as a structuring agent of cosmetic formulations. However, with the sustainability issues that are underway in the highly innovative cosmetic industry and with the growth prospects for the market of bio-based products, a much more prominent role is envisioned for BNC in this field. Thus, this review provides a comprehensive overview of the most recent (last 5 years) and relevant developments and challenges in the research of BNC applied to cosmetic, aiming at inspiring future research to go beyond in the applicability of this exceptional biotechnological material in such a promising area.

Cyanobacterial extracellular polymeric substances (EPS) are mainly composed of high-molecular-mass heteropolysaccharides, with variable composition and roles according to the microorganism and the environmental conditions. The number of constituents - both saccharidic and nonsaccharidic - and the complexity of structures give rise to speculations on how intricate their biosynthetic pathways could be, and how many genes may be involved in their production. However, little is known regarding the cyanobacterial EPS biosynthetic pathways and regulating factors. This review organizes available information on cyanobacterial EPS, including their composition, function and factors affecting their synthesis, and from the in silico analysis of available cyanobacterial genome sequences, proposes a putative mechanism for their biosynthesis.