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BACKGROUND: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-µg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS: BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS: Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).
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Vacunas contra la COVID-19 , COVID-19/prevención & control , Inmunogenicidad Vacunal , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/análisis , Vacuna BNT162 , COVID-19/epidemiología , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/inmunología , Niño , Femenino , Estudios de Seguimiento , Humanos , Inmunización Secundaria , Incidencia , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Método Simple Ciego , Resultado del Tratamiento , Adulto JovenRESUMEN
We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious ß-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.
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Antifúngicos/farmacología , Aspergillus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Glicósidos/química , Triterpenos/química , beta-Glucanos/metabolismo , Administración Oral , Animales , Antifúngicos/síntesis química , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Modelos Animales de Enfermedad , Glicósidos/farmacocinética , Glicósidos/farmacología , Glicósidos/uso terapéutico , Semivida , Ratones , Relación Estructura-Actividad , Triterpenos/farmacocinética , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
Our previously reported efforts to produce an orally active ß-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.
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Antifúngicos/química , Triazoles/química , beta-Glucanos/metabolismo , Administración Oral , Animales , Antifúngicos/metabolismo , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Modelos Animales de Enfermedad , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Glicósidos/química , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/metabolismo , Triazoles/farmacología , Triazoles/uso terapéutico , Triterpenos/química , beta-Glucanos/químicaRESUMEN
The clinical success of the echinocandins, which can only be administered parentally, has validated ß-1,3-glucan synthase (GS) as an antifungal target. Semi-synthetic modification of enfumafungin, a triterpene glycoside natural product, was performed with the aim of producing a new class of orally active GS inhibitors. Replacement of the C2 acetoxy moiety with various heterocycles did not improve GS or antifungal potency. However, replacement of the C3 glycoside with an aminoether moiety dramatically improved oral pharmacokinetic (PK) properties while maintaining GS and antifungal potency. Installing an aminotetrazole at C2 in conjunction with an N-alkylated aminoether at C3 produced derivatives with significantly improved GS and antifungal potency that exhibited robust oral efficacy in a murine model of disseminated candidiasis.
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Antifúngicos/química , Glicósidos/química , Triterpenos/química , beta-Glucanos/química , Administración Oral , Animales , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Aspergillus fumigatus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Candidiasis/veterinaria , Glucosiltransferasas/antagonistas & inhibidores , Glucosiltransferasas/metabolismo , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Relación Estructura-Actividad , Terpenos/química , beta-Glucanos/farmacocinética , beta-Glucanos/uso terapéuticoRESUMEN
Lyme disease (LD), caused by spirochete bacteria of the genus Borrelia burgdorferi sensu lato, remains the most common vector-borne disease in the northern hemisphere. Borrelia outer surface protein A (OspA) is an integral surface protein expressed during the tick cycle, and a validated vaccine target. There are at least 20 recognized Borrelia genospecies, that vary in OspA serotype. This study presents a new in silico sequence-based method for OspA typing using next-generation sequence data. Using a compiled database of over 400 Borrelia genomes encompassing the 4 most common disease-causing genospecies, we characterized OspA diversity in a manner that can accommodate existing and new OspA types and then defined boundaries for classification and assignment of OspA types based on the sequence similarity. To accommodate potential novel OspA types, we have developed a new nomenclature: OspA in silico type (IST). Beyond the ISTs that corresponded to existing OspA serotypes 1-8, we identified nine additional ISTs that cover new OspA variants in B. bavariensis (IST9-10), B. garinii (IST11-12), and other Borrelia genospecies (IST13-17). The IST typing scheme and associated OspA variants are available as part of the PubMLST Borrelia spp. database. Compared to traditional OspA serotyping methods, this new computational pipeline provides a more comprehensive and broadly applicable approach for characterization of OspA type and Borrelia genospecies to support vaccine development.
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Antígenos de Superficie , Proteínas de la Membrana Bacteriana Externa , Lipoproteínas , Enfermedad de Lyme , Proteínas de la Membrana Bacteriana Externa/genética , Enfermedad de Lyme/microbiología , Lipoproteínas/genética , Antígenos de Superficie/genética , Borrelia burgdorferi/genética , Borrelia burgdorferi/clasificación , Simulación por Computador , Humanos , Genoma Bacteriano , Grupo Borrelia Burgdorferi/genética , Grupo Borrelia Burgdorferi/clasificación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Serogrupo , Filogenia , Vacunas BacterianasRESUMEN
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus Mpro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six Mpro mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and Mpro activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.
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Antivirales , Tratamiento Farmacológico de COVID-19 , Farmacorresistencia Viral , Mutación , SARS-CoV-2 , SARS-CoV-2/genética , SARS-CoV-2/efectos de los fármacos , Farmacorresistencia Viral/genética , Humanos , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/virología , COVID-19/genética , COVID-19/epidemiología , Proteasas 3C de Coronavirus/genética , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Lactamas , Leucina , Nitrilos , ProlinaRESUMEN
Streptococcus pneumoniae (pneumococcus) is a leading cause of morbidity and mortality worldwide. Although multi-valent pneumococcal vaccines have curbed the incidence of disease, their introduction has resulted in shifted serotype distributions that must be monitored. Whole genome sequence (WGS) data provide a powerful surveillance tool for tracking isolate serotypes, which can be determined from nucleotide sequence of the capsular polysaccharide biosynthetic operon (cps). Although software exists to predict serotypes from WGS data, most are constrained by requiring high-coverage next-generation sequencing reads. This can present a challenge in respect of accessibility and data sharing. Here we present PfaSTer, a machine learning-based method to identify 65 prevalent serotypes from assembled S. pneumoniae genome sequences. PfaSTer combines dimensionality reduction from k-mer analysis with a Random Forest classifier for rapid serotype prediction. By leveraging the model's built-in statistical framework, PfaSTer determines confidence in its predictions without the need for coverage-based assessments. We then demonstrate the robustness of this method, returning >97â% concordance when compared to biochemical results and other in silico serotyping tools. PfaSTer is open source and available at: https://github.com/pfizer-opensource/pfaster.
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Streptococcus pneumoniae , Serogrupo , Serotipificación/métodos , Secuenciación Completa del Genoma , Secuencia de BasesRESUMEN
Malaria continues to have a significant impact on the health of the developing world. Efforts to combat this disease now focus on combination therapy in order to stem the emergence of resistant parasites. Continued efforts are needed to discover and develop new agents for use in combination antimalarial regimens. MK-4815 is a small molecule with antimalarial activity that was identified from a large pharmaceutical compound collection using a semiautomated version of a well-established in vitro assay for the erythrocytic stages of Plasmodium falciparum. In vitro studies indicate that the compound selectively accumulates in infected red blood cells and is most effective against the metabolically active late trophozoite/early schizont stages. A variety of drug-resistant field isolates of P. falciparum were found to be as sensitive to MK-4815 as the wild-type lines. MK-4815 is orally active in a P. berghei mouse model of acute malaria. In this model, where untreated animals succumb to infection 10 to 12 days postinfection, MK-4815 was completely curative when given as a single dose of 50 mg/kg, 2 doses of 25 mg/kg, or 4.5 doses of 12.5 mg/kg. In pharmacokinetic studies with mice and rhesus monkeys, MK-4815 demonstrated oral bioavailability and low clearance. In addition, MK-4815 is inexpensive to synthesize, an important characteristic for providing affordable antimalaria therapy to the developing world. The attractive biological and pharmaceutical profile of MK-4815 demonstrates its potential for use in combination with other agents in the fight against malaria.
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Antimaláricos/farmacología , Malaria/tratamiento farmacológico , Metilaminas/farmacocinética , Fenoles/farmacocinética , Plasmodium falciparum/efectos de los fármacos , Administración Oral , Animales , Antimaláricos/síntesis química , Antimaláricos/farmacocinética , Antimaláricos/uso terapéutico , Disponibilidad Biológica , Esquema de Medicación , Combinación de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Malaria/mortalidad , Malaria/parasitología , Metilaminas/síntesis química , Metilaminas/química , Ratones , Ratones Endogámicos BALB C , Fenoles/síntesis química , Fenoles/química , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/fisiología , Plasmodium falciparum/fisiología , Tasa de Supervivencia , Trofozoítos/efectos de los fármacos , Trofozoítos/fisiologíaRESUMEN
Orally bioavailable inhibitors of ß-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.
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Antifúngicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Glucosiltransferasas/antagonistas & inhibidores , Glicósidos/química , Triterpenos/química , Administración Oral , Animales , Antifúngicos/química , Antifúngicos/farmacocinética , Candida albicans/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Glucosiltransferasas/metabolismo , Glicósidos/síntesis química , Glicósidos/farmacocinética , Semivida , Ratones , Relación Estructura-Actividad , Triterpenos/síntesis química , Triterpenos/farmacocinéticaRESUMEN
INTRODUCTION: The two currently licensed surface protein non-capsular meningococcal serogroup B (MenB) vaccines both have the purpose of providing broad coverage against diverse MenB strains. However, the different antigen compositions and approaches used to assess breadth of coverage currently make direct comparisons complex. AREAS COVERED: In the second of two companion papers, we comprehensively review the serology and factors influencing breadth of coverage assessments for two currently licensed MenB vaccines. EXPERT OPINION: Surface protein MenB vaccines were developed using different approaches, resulting in unique formulations and thus their breadth of coverage. The surface proteins used as vaccine antigens can vary among meningococcal strains due to gene presence/absence, sequence diversity, and differences in protein expression. Assessment of the breadth of coverage provided by vaccines is influenced by the ability to induce cross-reactive functional immune responses to sequence diverse protein variants; the characteristics of the circulating invasive strains from specific geographic locations; methodological differences in the immunogenicity assays; differences in human immune responses between individuals; and the maintenance of protective antibody levels over time. Understanding the proportion of meningococcal strains, which are covered by the two licensed vaccines, is important in understanding protection from disease and public health use.
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Infecciones Meningocócicas , Vacunas Meningococicas , Neisseria meningitidis Serogrupo B , Neisseria meningitidis , Antígenos Bacterianos , Vacunas Bacterianas , Humanos , Proteínas de la Membrana , Infecciones Meningocócicas/prevención & controlRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to represent a global health emergency as a highly transmissible, airborne virus. An important coronaviral drug target for treatment of COVID-19 is the conserved main protease (Mpro). Nirmatrelvir is a potent Mpro inhibitor and the antiviral component of Paxlovid. The significant viral sequencing effort during the ongoing COVID-19 pandemic represented a unique opportunity to assess potential nirmatrelvir escape mutations from emerging variants of SARS-CoV-2. To establish the baseline mutational landscape of Mpro prior to the introduction of Mpro inhibitors, Mpro sequences and its cleavage junction regions were retrieved from ~4,892,000 high-quality SARS-CoV-2 genomes in the open-access Global Initiative on Sharing Avian Influenza Data (GISAID) database. Any mutations identified from comparison to the reference sequence (Wuhan-Hu-1) were catalogued and analyzed. Mutations at sites key to nirmatrelvir binding and protease functionality (e.g., dimerization sites) were still rare. Structural comparison of Mpro also showed conservation of key nirmatrelvir contact residues across the extended Coronaviridae family (α-, ß-, and γ-coronaviruses). Additionally, we showed that over time, the SARS-CoV-2 Mpro enzyme remained under purifying selection and was highly conserved relative to the spike protein. Now, with the emergency use authorization (EUA) of Paxlovid and its expected widespread use across the globe, it is essential to continue large-scale genomic surveillance of SARS-CoV-2 Mpro evolution. This study establishes a robust analysis framework for monitoring emergent mutations in millions of virus isolates, with the goal of identifying potential resistance to present and future SARS-CoV-2 antivirals. IMPORTANCE The recent authorization of oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals, such as Paxlovid, has ushered in a new era of the COVID-19 pandemic. The emergence of new variants, as well as the selective pressure imposed by antiviral drugs themselves, raises concern for potential escape mutations in key drug binding motifs. To determine the potential emergence of antiviral resistance in globally circulating isolates and its implications for the clinical response to the COVID-19 pandemic, sequencing of SARS-CoV-2 viral isolates before, during, and after the introduction of new antiviral treatments is critical. The infrastructure built herein for active genetic surveillance of Mpro evolution and emergent mutations will play an important role in assessing potential antiviral resistance as the pandemic progresses and Mpro inhibitors are introduced. We anticipate our framework to be the starting point in a larger effort for global monitoring of the SARS-CoV-2 Mpro mutational landscape.
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COVID-19 , SARS-CoV-2 , Animales , Antivirales/metabolismo , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/metabolismo , Combinación de Medicamentos , Humanos , Lactamas , Leucina , Nitrilos , Pandemias , Prolina , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Ritonavir , SARS-CoV-2/genética , Proteínas no Estructurales Virales/metabolismoRESUMEN
Protection conferred by pneumococcal polysaccharide conjugate vaccines (PCVs) is associated with PCV-induced antibodies against vaccine-covered serotypes that exhibit functional opsonophagocytic activity (OPA). Structural similarity between capsular polysaccharides of closely related serotypes may result in induction of cross-reactive antibodies with or without a cross-functional activity against a serotype not covered by a PCV, with the former providing an additional protective clinical benefit. Serotypes 15B, 15A, and 15C, in the serogroup 15, are among the most prevalent Streptococcus pneumoniae serotypes associated with invasive pneumococcal disease following the implementation of a 13-valent PCV; in addition, 15B contributes significantly to acute otitis media. Serological discrimination between closely related serotypes such as 15B and 15C is complicated; here, we implemented an algorithm to quickly differentiate 15B from its closely related serotypes 15C and 15A directly from whole-genome sequencing data. In addition, molecular dynamics simulations of serotypes 15A, 15B, and 15C polysaccharides demonstrated that while 15B and 15C polysaccharides assume rigid branched conformation, 15A polysaccharide assumes a flexible linear conformation. A serotype 15B conjugate, included in a 20-valent PCV (PCV20), induced cross-functional OPA serum antibody responses against the structurally similar serotype 15C but not against serotype 15A, both not included in PCV20. In PCV20-vaccinated adults (18-49 years), robust OPA antibody titers were detected against both serotypes 15B (the geometric mean titer [GMT] of 19,334) and 15C (GMTs of 1692 and 2747 for strains PFE344340 and PFE1160, respectively), but were negligible against serotype 15A (GMTs of 10 and 30 for strains PFE593551 and PFE647449, respectively). Cross-functional 15B/C responses were also confirmed using sera from a larger group of older adults (60-64 years).
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Infecciones Neumocócicas , Streptococcus pneumoniae , Anciano , Anticuerpos Antibacterianos , Humanos , Inmunidad , Infecciones Neumocócicas/prevención & control , Vacunas Neumococicas , Polisacáridos , Serogrupo , Vacunas ConjugadasRESUMEN
In a whole-cell mechanism of action (MOA)-based screening strategy for discovery of antifungal agents, Candida albicans was used, followed by testing of active extracts in the C. albicans fitness test (CaFT), which provides insight into the mechanism of action. A fermentation extract of an undescribed species of Metulocladosporiella that inhibited proteasome activity in a C. albicans fitness test was identified. The chemical genomic profile of the extract contained hypersensitivity of heterozygous deletion strains (strains that had one of the genes of the diploid genes knocked down) of genes represented by multiple subunits of the 25S proteasome. Two structurally related peptide aldehydes, named fellutamides C and D, were isolated from the extract. Fellutamides were active against C. albicans and Aspergillus fumigatus with MICs ranging from 4 to 16 µg/mL and against fungal proteasome (IC50 0.2 µg/mL). Both compounds showed proteasome activity against human tumor cell lines, potently inhibiting the growth of PC-3 prostate carcinoma cells, but not A549 lung carcinoma cells. In PC-3 cells compound treatment produced a G2M cell cycle block and induced apoptosis. Preliminary SAR studies indicated that the aldehyde group is critical for the antifungal activity and that the two hydroxy groups are quantitatively important for potency.
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Antifúngicos , Ascomicetos/química , Candida albicans/efectos de los fármacos , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Fase G2/efectos de los fármacos , Humanos , Masculino , Estructura Molecular , Oligopéptidos/química , Oligopéptidos/aislamiento & purificación , Oligopéptidos/farmacología , Relación Estructura-ActividadRESUMEN
A Staphylococcus aureus four-antigen vaccine (SA4Ag) was designed for the prevention of invasive disease in surgical patients. The vaccine is composed of capsular polysaccharide type 5 and type 8 CRM197 conjugates, a clumping factor A mutant (Y338A-ClfA) and manganese transporter subunit C (MntC). S. aureus pathogenicity is characterized by an ability to rapidly adapt to the host environment during infection, which can progress from a local infection to sepsis and invasion of distant organs. To test the protective capacity of the SA4Ag vaccine against progressive disease stages of an invasive S. aureus infection, a deep tissue infection mouse model, a bacteremia mouse model, a pyelonephritis model, and a rat model of infectious endocarditis were utilized. SA4Ag vaccination significantly reduced the bacterial burden in deep tissue infection, in bacteremia, and in the pyelonephritis model. Complete prevention of infection was demonstrated in a clinically relevant endocarditis model. Unfortunately, these positive preclinical findings with SA4Ag did not prove the clinical utility of SA4Ag in the prevention of surgery-associated invasive S. aureus infection.
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Neisseria meningitidis, the causative agent of invasive meningococcal disease (IMD), is classified into different serogroups defined by their polysaccharide capsules. Meningococcal serogroups A, B, C, W, and Y are responsible for most IMD cases, with serogroup B (MenB) causing a substantial percentage of IMD cases in many regions. Vaccines using capsular polysaccharides conjugated to carrier proteins have been successfully developed for serogroups A, C, W, and Y. However, because the MenB capsular polysaccharide is poorly immunogenic, MenB vaccine development has focused on alternative antigens. The 2 currently available MenB vaccines (MenB-4C and MenB-FHbp) both include factor H binding protein (FHbp), a surface-exposed protein harboured by nearly all meningococcal isolates that is important for survival of the bacteria in human blood. MenB-4C contains a nonlipidated FHbp from subfamily B in addition to other antigens, including Neisserial Heparin Binding Antigen, Neisserial adhesin A, and outer membrane vesicles, whereas MenB-FHbp contains a lipidated FHbp from each subfamily (A and B). FHbp is highly immunogenic and a main target of bactericidal activity of antibodies elicited by both licensed MenB vaccines. FHbp is also an important vaccine component, in contrast to some other meningococcal antigens that may have limited cross-protection across strains, as FHbp-specific antibodies can provide broad cross-protection within each subfamily. Limited cross-protection between subfamilies necessitates the inclusion of FHbp variants from both subfamilies to achieve broad FHbp-based vaccine coverage. Additionally, immune responses to the lipidated form of FHbp have a superior cross-reactive profile to those elicited by the nonlipidated form. Taken together, the inclusion of lipidated FHbp variants from both FHbp subfamilies is expected to provide broad protection against the diverse disease-causing meningococcal strains expressing a wide range of FHbp sequence variants. This review describes the development of vaccines for MenB disease prevention, with a focus on the FHbp antigen.
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Infecciones Meningocócicas , Vacunas Meningococicas , Neisseria meningitidis Serogrupo B , Neisseria meningitidis , Antígenos Bacterianos , Proteínas Bacterianas/genética , Proteínas Portadoras , Factor H de Complemento , Humanos , Infecciones Meningocócicas/prevención & controlRESUMEN
Clostridioides (Clostridium) difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings. Currently there is no vaccine to prevent initial or recurrent C. difficile infection (CDI). Two large clostridial toxins, TcdA and TcdB, are the primary virulence factors for CDI. Immunological approaches to prevent CDI include antibody-mediated neutralization of the cytotoxicity of these toxins. An understanding of the sequence diversity of the two toxins expressed by disease causing isolates is critical for the interpretation of the immune response to the toxins. In this study, we determined the whole genome sequence (WGS) of 478 C. difficile isolates collected in 12 countries between 2004 and 2018 to probe toxin variant diversity. A total of 44 unique TcdA variants and 37 unique TcdB variants were identified. The amino acid sequence conservation among the TcdA variants (≥98%) is considerably greater than among the TcdB variants (as low as 86.1%), suggesting that different selection pressures may have contributed to the evolution of the two toxins. Phylogenomic analysis of the WGS data demonstrate that isolates grouped together based on ribotype or MLST code for multiple different toxin variants. These findings illustrate the importance of determining not only the ribotype but also the toxin sequence when evaluating strain coverage using vaccine strategies that target these virulence factors. We recommend that toxin variant type and sequence type (ST), be used together with ribotype data to provide a more comprehensive strain classification scheme for C. difficile surveillance during vaccine development objectives.
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BACKGROUND: Invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) remains a health risk in Canada and globally. Two MenB vaccines are now approved for use. An understanding of the genotype of Canadian strains and the potential strain coverage conferred by the MenB-FHbp vaccine is needed to inform immunization policies. METHODS: Serogroup B Neisseria meningitidis strains responsible for meningococcal disease in Canada from 2006 to 2012 were collected as part of the Canadian Immunization Monitoring Program Active surveillance network. Genotypic analysis was done on MenB isolates from 2006 to 2012 with determination of fHbp surface expression for a subset of isolates: those occurring from 2010 to 2012. RESULTS: Two clonal complexes (cc269 and cc41/44) were observed in 68.8% of the 276 isolates. A total of 50 different fHbp peptides were identified among isolates from 2006 to 2012. Surface expression of fHbp was detected on 95% of MenB isolates from 2010 to 2012 and 91% of isolates expressed fHbp at levels that are predicted to be susceptible to the bactericidal immune response elicited by the MenB-FHbp vaccine. Some regional differences were observed, particularly in isolates from British Columbia and Quebec. CONCLUSION: The majority of MenB isolates responsible for meningococcal disease in Canada expressed fHbp at levels predicted to be sufficient for complement mediated bactericidal activity in the presence of MenB-FHbp induced serum antibodies.
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Infecciones Meningocócicas , Vacunas Meningococicas/inmunología , Neisseria meningitidis Serogrupo B , Anticuerpos Antibacterianos/sangre , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Colombia Británica , Humanos , Infecciones Meningocócicas/epidemiología , Infecciones Meningocócicas/prevención & control , Neisseria meningitidis Serogrupo B/genética , Neisseria meningitidis Serogrupo B/inmunología , Quebec , SerogrupoRESUMEN
Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.
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Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida albicans/genética , Evaluación Preclínica de Medicamentos/métodos , Polinucleotido Adenililtransferasa/antagonistas & inhibidores , Alelos , Secuencia de Aminoácidos , Animales , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/crecimiento & desarrollo , Aspergillus fumigatus/metabolismo , Productos Biológicos/química , Productos Biológicos/aislamiento & purificación , Candida albicans/metabolismo , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Mezclas Complejas/farmacología , Desoxiadenosinas/metabolismo , Desoxiadenosinas/farmacología , Farmacorresistencia Fúngica , Fermentación , Heterocigoto , Ratones , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mutación , Poliadenilación/efectos de los fármacos , Polinucleotido Adenililtransferasa/genética , Polinucleotido Adenililtransferasa/metabolismo , ARN Mensajero/metabolismo , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/metabolismo , Resultado del TratamientoRESUMEN
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Asunto(s)
Coccidiostáticos/síntesis química , Indoles/síntesis química , Animales , Coccidiosis/tratamiento farmacológico , Coccidiosis/enzimología , Coccidiosis/parasitología , Coccidiostáticos/farmacología , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Eimeria tenella/efectos de los fármacos , Eimeria tenella/enzimología , Eimeria tenella/crecimiento & desarrollo , Indoles/farmacología , Aves de Corral/parasitología , Piridinas/síntesis químicaRESUMEN
We isolated a cyclic lipodepsipeptide, phomafungin, from a Phoma sp. The distinct antifungal activity of phomafungin in the crude extract was initially discovered by mechanistic profiling in the Candida albicans fitness test. The purified compound contains a 28 member ring consisting of eight amino acids and a beta-hydroxy-gamma-methyl-hexadecanoic acid, and displays a broad spectrum of antifungal activity against Candida spp., Aspergillus fumigatus and Trichophyton mentagrophytes with MIC of 2-8 microg/ml, and toxicity to mice at 25 mg/kg. The linear peptide derived from opening of the lactone ring was devoid of antifungal activity as well as toxicity. Phomafungin has been identified in a number of Phoma spp. collected from Africa and the Indian and Pacific Ocean islands.