Synthesis of Multicomponent Peptide-Based Vaccine Candidates against Group A Streptococcus

2017 ◽  
Vol 70 (2) ◽  
pp. 184
Author(s):  
Waleed M. Hussein ◽  
Jiaxin Xu ◽  
Pavla Simerska ◽  
Istvan Toth
Keyword(s):  
Vaccine Candidate ◽  
Group A Streptococcus ◽  
Cycloaddition Reaction ◽  
Bacterial Pathogen ◽  
T Helper ◽  
Toxic Shock ◽  
Helper Epitope ◽  
Invasive Infections ◽  
Group A ◽  
Universal Expression

Group A streptococcus (GAS; Streptococcus pyogenes), known as the ‘flesh-eating bacterium’, is a human bacterial pathogen that normally causes benign infections (e.g. sore throat and pyoderma), but is also responsible for severe invasive infections (e.g. ‘flesh-eating’ disease and toxic shock syndrome), heart disease, and kidney failure. A safe commercial GAS vaccine is yet to be developed. Individual GAS antigens demonstrate potential universal expression across all GAS serotypes (>200 known), with dramatically reduced concern for autoimmune complications, and compelling efficacy in preclinical testing in mice. In this study, we developed a stepwise conjugation strategy, copper-catalysed alkyne–azide cycloaddition reaction (CuAAC), followed by mercapto–maleimide conjugation, to synthesise a multiantigenic, self-adjuvanting, peptide-based vaccine candidate against GAS. This multiantigenic vaccine includes two GAS antigens, J8 and NS1, a T-helper epitope, PADRE, and a self-adjuvanting moiety, dipalmitoyl serine.

scholarly journals Convergent synthetic methodology for the construction of self-adjuvanting lipopeptide vaccines using a novel carbohydrate scaffold

2014 ◽  
Vol 10 ◽  
pp. 1741-1748 ◽  
Author(s):  
Vincent Fagan ◽  
Istvan Toth ◽  
Pavla Simerska
Keyword(s):  
Vaccine Candidate ◽  
Cycloaddition Reaction ◽  
Cell Epitope ◽  
T Helper ◽  
Synthetic Strategy ◽  
B Cell Epitope ◽  
Helper Epitope ◽  
Construction Of Self ◽  
Group A ◽  
Glucose Derivative

A novel convergent synthetic strategy for the construction of multicomponent self-adjuvanting lipopeptide vaccines was developed. A tetraalkyne-functionalized glucose derivative and lipidated Fmoc-lysine were prepared by novel efficient and convenient syntheses. The carbohydrate building block was coupled to the self-adjuvanting lipidic moiety (three lipidated Fmoc-lysines) on solid support. Four copies of a group A streptococcal B cell epitope (J8) were then conjugated to the glyco-lipopeptide using a copper-catalyzed cycloaddition reaction. The approach was elaborated by the preparation of a second vaccine candidate which incorporated an additional promiscuous T-helper epitope.

scholarly journals Distribution of emm type and antibiotic susceptibility of group A streptococci causing invasive and noninvasive disease

2008 ◽  
Vol 57 (11) ◽  
pp. 1383-1388 ◽  
Author(s):  
Takeaki Wajima ◽  
Somay Y. Murayama ◽  
Katsuhiko Sunaoshi ◽  
Eiichi Nakayama ◽  
Keisuke Sunakawa ◽  
...  
Keyword(s):  
Streptococcus Pyogenes ◽  
Macrolide Antibiotic ◽  
Group A Streptococcus ◽  
Acute Otitis Media ◽  
Toxic Shock ◽  
Medical Institutions ◽  
Invasive Infections ◽  
Group A ◽  
Resistant Strains ◽  
Emm Type

To determine the prevalence of macrolide antibiotic and levofloxacin resistance in infections with Streptococcus pyogenes (group A streptococcus or GAS), strains were collected from 45 medical institutions in various parts of Japan between October 2003 and September 2006. Four hundred and eighty-two strains from patients with GAS infections were characterized genetically. Strains were classified into four groups according to the type of infection: invasive infections (n=74) including sepsis, cellulitis and toxic-shock-like syndrome; acute otitis media (AOM; n=23); abscess (n=53); and pharyngotonsillitis (n=332). Among all strains, 32 emm types were identified; emm1 was significantly more common in invasive infections (39.2 %) and AOM (43.5 %) than in abscesses (3.8 %) or pharyngotonsillitis (10.2 %). emm12 and emm4 each accounted for 23.5 % of pharyngotonsillitis cases. Susceptibility of GAS strains to eight β-lactam agents was excellent, with MICs of 0.0005–0.063 μg ml−1. Macrolide-resistant strains accounted for 16.2 % of all strains, while the percentages of strains possessing the resistance genes erm(A), erm(B) and mef(A) were 2.5 %, 6.2 % and 7.5 %, respectively. Although no strains with high resistance to levofloxacin were found, strains with an MIC of 2–4 μg ml−1 (17.4 %) had amino acid substitutions at either Ser-79 or Asp-83 in ParC. These levofloxacin-intermediately resistant strains included 16 emm types, but macrolide-resistant strains were more likely than others to represent certain emm types.

scholarly journals Functional analysis of a group A streptococcal glycoside hydrolase Spy1600 from family 84 reveals it is a β-N-acetylglucosaminidase and not a hyaluronidase

2006 ◽  
Vol 399 (2) ◽  
pp. 241-247 ◽  
Author(s):  
William L. Sheldon ◽  
Matthew S. Macauley ◽  
Edward J. Taylor ◽  
Charlotte E. Robinson ◽  
Simon J. Charnock ◽  
...  
Keyword(s):  
Glycoside Hydrolase ◽  
Catalytic Mechanism ◽  
Group A Streptococcus ◽  
Competitive Inhibitor ◽  
Glycoside Hydrolases ◽  
Glycoside Hydrolase Family ◽  
Toxic Shock ◽  
Nmr Studies ◽  
Invasive Infections ◽  
Group A

Group A streptococcus (Streptococcus pyogenes) is the causative agent of severe invasive infections such as necrotizing fasciitis (the so-called ‘flesh eating disease’) and toxic-shock syndrome. Spy1600, a glycoside hydrolase from family 84 of the large superfamily of glycoside hydrolases, has been proposed to be a virulence factor. In the present study we show that Spy1600 has no activity toward galactosaminides or hyaluronan, but does remove β-O-linked N-acetylglucosamine from mammalian glycoproteins – an observation consistent with the inclusion of eukaryotic O-glycoprotein 2-acetamido-2-deoxy-β-D-glucopyranosidases within glycoside hydrolase family 84. Proton NMR studies, structure–reactivity studies for a series of fluorinated analogues and analysis of 1,2-dideoxy-2′-methyl-α-D-glucopyranoso-[2,1-d]-Δ2′-thiazoline as a competitive inhibitor reveals that Spy1600 uses a double-displacement mechanism involving substrate-assisted catalysis. Family 84 glycoside hydrolases are therefore comprised of both prokaryotic and eukaryotic β-N-acetylglucosaminidases using a conserved catalytic mechanism involving substrate-assisted catalysis. Since these enzymes do not have detectable hyaluronidase activity, many family 84 glycoside hydrolases are most likely incorrectly annotated as hyaluronidases.

scholarly journals Identification and Characterization of Serotype-Specific Variation in Group A Streptococcus Pilus Expression

2017 ◽  
Vol 86 (2) ◽  
Author(s):  
Gregory Calfee ◽  
Jessica L. Danger ◽  
Ira Jain ◽  
Eric W. Miller ◽  
Poulomee Sarkar ◽  
...  
Keyword(s):  
Human Blood ◽  
Vaccine Development ◽  
Group A Streptococcus ◽  
Bacterial Pathogen ◽  
Host Cells ◽  
Dependent Manner ◽  
Content Type ◽  
Low Level ◽  
Invasive Infections ◽  
Group A

ABSTRACTIsolates of a given bacterial pathogen often display phenotypic variation, and this can negatively impact public health, for example, by reducing the efficacy of preventative measures. Here, we identify that the human pathogen group AStreptococcus(GAS;Streptococcus pyogenes) expresses pili on its cell surface in a serotype-specific manner. Specifically, we show that serotype M3 GAS isolates, which are nonrandomly associated with causing particularly severe and lethal invasive infections, produce negligible amounts of pili relative to serotype M1 and M49 isolates. Performance of an interserotype transcriptome comparison (serotype M1 versus serotype M3) was instrumental in this discovery. We also identified that the transcriptional regulator Nra positively regulates pilus expression in M3 GAS isolates and that the low level of pilus expression of these isolates correlates with a low level ofnratranscription. Finally, we discovered that the phenotypic consequences of low levels of pilus expression by M3 GAS isolates are a reduced ability to adhere to host cells and an increased ability to survive and proliferate in human blood. We propose that an enhanced ability to survive in human blood, in part due to reduced pilus expression, is a contributing factor in the association of serotype M3 isolates with highly invasive infections. In conclusion, our data show that GAS isolates express pili in a serotype-dependent manner and may inform vaccine development, given that pilus proteins are being discussed as possible GAS vaccine antigens.

scholarly journals Playing With Fire: Proinflammatory Virulence Mechanisms of Group A Streptococcus

2021 ◽  
Vol 11 ◽  
Author(s):  
Shyra Wilde ◽  
Anders F. Johnson ◽  
Christopher N. LaRock
Keyword(s):  
Virulence Factors ◽  
Group A Streptococcus ◽  
Severe Disease ◽  
Fatal Outcome ◽  
Toxic Shock ◽  
Autoreactive Antibodies ◽  
Invasive Infections ◽  
Group A ◽  
Disease Understanding

Group A Streptococcus is an obligate human pathogen that is a major cause of infectious morbidity and mortality. It has a natural tropism for the oropharynx and skin, where it causes infections with excessive inflammation due to its expression of proinflammatory toxins and other virulence factors. Inflammation directly contributes to the severity of invasive infections, toxic shock syndrome, and the induction of severe post-infection autoimmune disease caused by autoreactive antibodies. This review discusses what is known about how the virulence factors of Group A Streptococcus induce inflammation and how this inflammation can promote disease. Understanding of streptococcal pathogenesis and the role of hyper-immune activation during infection may provide new therapeutic targets to treat the often-fatal outcome of severe disease.

Development of a DNA aptamer that binds specifically to group A Streptococcus serotype M3

2017 ◽  
Vol 63 (2) ◽  
pp. 160-168 ◽  
Author(s):  
Hanif Alfavian ◽  
Seyed Latif Mousavi Gargari ◽  
Samaneh Rasoulinejad ◽  
Arvin Medhat
Keyword(s):  
Group A Streptococcus ◽  
Dna Aptamer ◽  
Live Cells ◽  
Streptococcal Toxic Shock Syndrome ◽  
Toxic Shock ◽  
Apparent Dissociation Constant ◽  
Invasive Infections ◽  
Group A ◽  
High Degree ◽  
High Binding Affinity

Group A streptococcus (GAS) is an important Gram-positive pathogen that causes various human diseases ranging from peripheral lesions to invasive infections. The M protein is one of the main virulence factors present on the cell surface and is associated with invasive GAS infections. Compared with other M types, serotype M3 has a predominant role in lethal infections and demonstrates epidemic behaviors, including streptococcal toxic shock syndrome, bacteremia, and necrotizing fasciitis. Traditional methods for M typing are time-consuming, tedious, contradictory, and generally restricted to reference laboratories. Therefore, development of a new M-typing technique is needed. Aptamers with the ability to detect their target with a high degree of accuracy and specificity can be ideal candidates for specific M-typing of Streptococcus pyogenes. In this study DNA aptamers with a high binding affinity towards S. pyogenes serotype M3 were selected through 12 iterative rounds of the Systematic Evolution of Ligands by EXponential (SELEX) enrichment procedure using live cells as a target. We monitored the progress of the SELEX procedure by flow cytometry analysis. Of several aptamer sequences analyzed, 12L18A showed the highest binding efficiency towards S. pyogenes type M3, with an apparent dissociation constant (Kd) of 7.47 ± 1.72 pmol/L being the lowest. Therefore the isolated aptamer can be used in any tool, such as a biosensor, for the detection of S. pyogenes and can be used in the development of a novel M-typing system.

scholarly journals Biochemical and biological activity of arginine deiminase from Streptococcus pyogenes M22

2016 ◽  
Vol 94 (2) ◽  
pp. 129-137 ◽  
Author(s):  
Eleonora A. Starikova ◽  
Alexey V. Sokolov ◽  
Anna Yu. Vlasenko ◽  
Larisa A. Burova ◽  
Irina S. Freidlin ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Streptococcus Pyogenes ◽  
Group A Streptococcus ◽  
Bacterial Pathogen ◽  
Arginine Deiminase ◽  
Dependent Manner ◽  
Group A ◽  
Micro Organisms ◽  
Dose Dependent

Streptococcus pyogenes (group A Streptococcus; GAS) is an important gram-positive extracellular bacterial pathogen responsible for a number of suppurative infections. This micro-organism has developed complex virulence mechanisms to avoid the host’s defenses. We have previously reported that SDSC from GAS type M22 causes endothelial-cell dysfunction, and inhibits cell adhesion, migration, metabolism, and proliferation in a dose-dependent manner, without affecting cell viability. This work aimed to isolate and characterize a component from GAS type M22 supernatant that suppresses the proliferation of endothelial cells (EA.hy926). In the process of isolating a protein possessing antiproliferative activity we identified arginine deiminase (AD). Further study showed that this enzyme is most active at pH 6.8. Calculating Km and Vmax gave the values of 0.67 mmol·L–1 and 42 s−1, respectively. A distinctive feature of AD purified from GAS type M22 is that its optimum activity and the maximal rate of the catalytic process is close to neutral pH by comparison with enzymes from other micro-organisms. AD from GAS type M22 suppressed the proliferative activity of endothelial cells in a dose-dependent mode. At the same time, in the presence of AD, the proportion of cells in G0/G1 phase increased. When l-Arg was added at increasing concentrations to the culture medium containing AD (3 μg·mL–1), the enzyme’s capacity to inhibit cell proliferation became partially depressed. The proportion of cells in phases S/G2 increased concomitantly, although the cells did not fully recover their proliferation activity. This suggests that AD from GAS type M22 has potential for the suppression of excessive cell proliferation.

Diverse disease processes of group A Streptococcus infection including severe invasive infections among members of a family

2021 ◽  
Vol 14 (4) ◽  
pp. e241339
Author(s):  
Kaori Amari ◽  
Masaki Tago ◽  
Naoko E Katsuki ◽  
Shu-ichi Yamashita
Keyword(s):  
Septic Shock ◽  
Distress Syndrome ◽  
Clinical Course ◽  
Group A Streptococcus ◽  
Bloody Stool ◽  
Laryngeal Oedema ◽  
Invasive Infections ◽  
Group A ◽  
The Right ◽  
Close Contacts

We herein report three cases of group A Streptococcus (GAS) infection in a family. Patient 1, a 50-year-old woman, was transferred to our hospital in shock with acute respiratory distress syndrome, swelling in the right neck and erythemata on both lower extremities. She required intubation because of laryngeal oedema. At the same time, patient 2, a 48-year-old man, was admitted because of septic shock, pneumonia and a pulmonary abscess. Five days later, patient 3, a 91-year-old woman, visited our clinic with bloody stool. All three patients were cured by antibiotics, and GAS was detected by specimen cultures. During these patients’ clinical course, an 84-year-old woman was found dead at home after having been diagnosed with type A influenza. All four patients lived in the same apartment. The GAS genotypes detected in the first three patients were identical. When treating patients with GAS, appropriate management of close contacts is mandatory.

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