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1.
Clin Infect Dis ; 75(12): 2079-2087, 2022 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-35521791

RESUMEN

BACKGROUND: While diagnostic, therapeutic, and vaccine development in the coronavirus disease 2019 (COVID-19) pandemic has proceeded at unprecedented speed, critical gaps in our understanding of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain unaddressed by current diagnostic strategies. METHODS: A statistical classifier for identifying prior SARS-CoV-2 infection was trained using >4000 SARS-CoV-2-associated T-cell receptor (TCR) ß sequences identified by comparing 784 cases and 2447 controls from 5 independent cohorts. The T-Detect COVID (Adaptive Biotechnologies) assay applies this classifier to TCR repertoires sequenced from blood samples to yield a binary assessment of past infection. Assay performance was assessed in 2 retrospective (n = 346; n = 69) and 1 prospective cohort (n = 87) to determine positive percent agreement (PPA) and negative percent agreement (NPA). PPA was compared with 2 commercial serology assays, and pathogen cross-reactivity was evaluated. RESULTS: T-Detect COVID demonstrated high PPA in individuals with prior reverse transcription-polymerase chain reaction (RT-PCR)-confirmed SARS-CoV-2 infection (97.1% 15+ days from diagnosis; 94.5% 15+ days from symptom onset), high NPA (∼100%) in presumed or confirmed SARS-CoV-2 negative cases, equivalent or higher PPA than 2 commercial serology tests, and no evidence of pathogen cross-reactivity. CONCLUSIONS: T-Detect COVID is a novel T-cell immunosequencing assay demonstrating high clinical performance for identification of recent or prior SARS-CoV-2 infection from blood samples, with implications for clinical management, risk stratification, surveillance, and understanding of protective immunity and long-term sequelae.


Asunto(s)
COVID-19 , Humanos , COVID-19/diagnóstico , SARS-CoV-2 , Prueba de COVID-19 , Estudios Retrospectivos , Estudios Prospectivos , Técnicas de Laboratorio Clínico , Sensibilidad y Especificidad , Receptores de Antígenos de Linfocitos T
2.
Antimicrob Agents Chemother ; 50(6): 2178-84, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16723580

RESUMEN

LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for Escherichia coli. These molecules did not inhibit the growth of Pseudomonas aeruginosa and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for P. aeruginosa raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the lpxC gene of P. aeruginosa under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for P. aeruginosa. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a P. aeruginosa construct in which the endogenous lpxC gene was inactivated and in which LpxC activity was supplied by the lpxC gene from E. coli. Conversely, an E. coli construct in which growth was dependent on the P. aeruginosa lpxC gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the E. coli enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate P. aeruginosa LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Antibacterianos/farmacología , Pseudomonas aeruginosa/efectos de los fármacos , Amidohidrolasas/química , Amidohidrolasas/genética , Amidohidrolasas/aislamiento & purificación , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Catálisis , Secuencia Conservada , Escherichia coli/enzimología , Escherichia coli/genética , Genes Bacterianos , Histidina/química , Lípido A/biosíntesis , Datos de Secuencia Molecular , Estructura Molecular , Mutación , Oxazoles/química , Oxazoles/farmacología , Fenilalanina/química , Regiones Promotoras Genéticas , Pseudomonas aeruginosa/genética , Reproducibilidad de los Resultados , Homología de Secuencia de Aminoácido , Zinc/química
3.
J Med Chem ; 45(14): 3112-29, 2002 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-12086497

RESUMEN

Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.


Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Oxazinas/síntesis química , Oxazoles/síntesis química , Pseudomonas aeruginosa/enzimología , Tiazoles/síntesis química , Técnicas Químicas Combinatorias , Inhibidores Enzimáticos/química , Oxazinas/química , Oxazoles/química , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/química
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