Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Más filtros










Base de datos
Intervalo de año de publicación
1.
Antimicrob Agents Chemother ; 65(12): e0091921, 2021 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-34516248

RESUMEN

Staphylococcus aureus is a serious threat to public health due to the rise of antibiotic resistance in this organism, which can prolong or exacerbate skin and soft tissue infections (SSTIs). Methicillin-resistant S. aureus is a Gram-positive bacterium and a leading cause of SSTIs. As such, many efforts are under way to develop therapies that target essential biological processes in S. aureus. Antimicrobial photodynamic therapy is an effective alternative to antibiotics; therefore we developed an approach to simultaneously expose S. aureus to intracellular and extracellular photosensitizers. A near infrared photosensitizer was conjugated to human monoclonal antibodies (MAbs) that target the S. aureus iron-regulated surface determinant (Isd) heme acquisition proteins. In addition, the compound VU0038882 was developed to increase photoactivatable porphyrins within the cell. Combinatorial photodynamic treatment of drug-resistant S. aureus exposed to VU0038882 and conjugated anti-Isd MAbs proved to be an effective antibacterial strategy in vitro and in a murine model of SSTIs.


Asunto(s)
Staphylococcus aureus Resistente a Meticilina , Infecciones de los Tejidos Blandos , Infecciones Estafilocócicas , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Humanos , Ratones , Fármacos Fotosensibilizantes/farmacología , Infecciones de los Tejidos Blandos/tratamiento farmacológico , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus
2.
Toxins (Basel) ; 12(6)2020 06 19.
Artículo en Inglés | MEDLINE | ID: mdl-32575633

RESUMEN

Staphylococcus aureus asymptomatically colonizes approximately 30-50% of the population and is a leading cause of bacteremia, bone/joint infections, and skin infections in the US. S. aureus has become a major public health threat due to antibiotic resistance and an increasing number of failed vaccine attempts. To develop new anti-staphylococcal preventive therapies, it will take a more thorough understanding of the current role S. aureus virulence factors play in contributing to human disease. This review focuses on the clinical association of individual toxins with S. aureus infection as well as attempted treatment options. Further understanding of these associations will increase understanding of toxins and their importance to S. aureus pathogenesis.


Asunto(s)
Toxinas Bacterianas/metabolismo , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/metabolismo , Factores de Virulencia/metabolismo , Interacciones Huésped-Patógeno , Humanos , Infecciones Estafilocócicas/epidemiología , Staphylococcus aureus/patogenicidad
3.
mBio ; 10(5)2019 10 22.
Artículo en Inglés | MEDLINE | ID: mdl-31641091

RESUMEN

Staphylococcus aureus is an important human pathogen that infects nearly every human tissue. Like most organisms, the acquisition of nutrient iron is necessary for its survival. One route by which it obtains this metal is through the iron-regulated surface determinant (Isd) system that scavenges iron from the hemoglobin of the host. We show that the heavy chain variable region IGHV1-69 gene commonly encodes human monoclonal antibodies (mAbs) targeting IsdB-NEAT2. Remarkably, these antibodies bind to multiple antigenic sites. One class of IGHV1-69-encoded mAbs blocks S. aureus heme acquisition by binding to the heme-binding site of NEAT2, while two additional classes reduce the bacterial burden in vivo by an alternative Fc receptor-mediated mechanism. We further identified clonal lineages of IGHV1-69-encoded mAbs using donor samples, showing that each lineage diversifies during infection by somatic hypermutation. These studies reveal that IGHV1-69-encoded antibodies contribute to a protective immune response, furthering our understanding of the correlates of protection against S. aureus infection.IMPORTANCE The human pathogen Staphylococcus aureus causes a wide range of infections, including skin abscesses and sepsis. There is currently no licensed vaccine to prevent S. aureus infection, and its treatment has become increasingly difficult due to antibiotic resistance. One potential way to inhibit S. aureus pathogenesis is to prevent iron acquisition. The iron-regulated surface determinant (Isd) system has evolved in S. aureus to acquire hemoglobin from the human host as a source of heme-iron. In this study, we investigated the molecular and structural basis for antibody-mediated correlates against a member of the Isd system, IsdB. The association of immunoglobulin heavy chain variable region IGHV1-69 gene-encoded human monoclonal antibodies with the response against S. aureus IsdB is described using structural and functional studies to define the importance of this antibody class. We also determine that somatic hypermutation in the development of these antibodies hinders rather than fine-tunes the immune response to IsdB.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Staphylococcus aureus/efectos de los fármacos , Inmunidad Adaptativa , Anticuerpos Monoclonales/química , Cristalografía por Rayos X , Humanos , Inmunidad Humoral , Proteómica , Staphylococcus aureus/metabolismo
4.
J Infect Dis ; 219(8): 1264-1273, 2019 04 08.
Artículo en Inglés | MEDLINE | ID: mdl-30496483

RESUMEN

The nutrient metal iron plays a key role in the survival of microorganisms. The iron-regulated surface determinant (Isd) system scavenges heme-iron from the human host, enabling acquisition of iron in iron-deplete conditions in Staphylococcus aureus during infection. The cell surface receptors IsdB and IsdH bind hemoproteins and transfer heme to IsdA, the final surface protein before heme-iron is transported through the peptidoglycan. To define the human B-cell response to IsdA, we isolated human monoclonal antibodies (mAbs) specific to the surface Isd proteins and determined their mechanism of action. We describe the first isolation of fully human IsdA and IsdH mAbs, as well as cross-reactive Isd mAbs. Two of the identified IsdA mAbs worked in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. Their protection was a result of both heme-blocking and Fc-mediated effector functions, underscoring the importance of targeting S. aureus using diverse mechanisms.


Asunto(s)
Anticuerpos Monoclonales/inmunología , Antígenos Bacterianos/inmunología , Hemoproteínas/inmunología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus/inmunología , Animales , Proteínas Bacterianas , Modelos Animales de Enfermedad , Femenino , Humanos , Espectrometría de Masas de Intercambio de Hidrógeno-Deuterio , Ratones , Ratones Endogámicos BALB C , Receptores de Superficie Celular/inmunología
5.
Microbiol Spectr ; 6(6)2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30547858

RESUMEN

Staphylococcus aureus is one of the most important human pathogens that is responsible for a variety of diseases ranging from skin and soft tissue infections to endocarditis and sepsis. In recent decades, the treatment of staphylococcal infections has become increasingly difficult as the prevalence of multi-drug resistant strains continues to rise. With increasing mortality rates and medical costs associated with drug resistant strains, there is an urgent need for alternative therapeutic options. Many innovative strategies for alternative drug development are being pursued, including disruption of biofilms, inhibition of virulence factor production, bacteriophage-derived antimicrobials, anti-staphylococcal vaccines, and light-based therapies. While many compounds and methods still need further study to determine their feasibility, some are quickly approaching clinical application and may be available in the near future.


Asunto(s)
Antibacterianos/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/uso terapéutico , Anticuerpos Antibacterianos/farmacología , Bacteriófagos/fisiología , Biopelículas/efectos de los fármacos , Descubrimiento de Drogas , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Humanos , Terapia de Fagos/métodos , Fotoquimioterapia/métodos , Percepción de Quorum/efectos de los fármacos , Staphylococcus aureus/patogenicidad , Virulencia/efectos de los fármacos , Factores de Virulencia
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...