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1.
Sci Rep ; 11(1): 23447, 2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34873199

RESUMEN

The emergence of infections by carbapenem resistant Enterobacteriaceae (CRE) pathogens has created an urgent public health threat, as carbapenems are among the drugs of last resort for infections caused by a growing fraction of multi-drug resistant (MDR) bacteria. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. Here, we report on the efficacy of a novel macrocyclic peptide, minimized theta-defensin (MTD)-12813 in CRE sepsis. MTD12813 is a theta-defensin inspired cyclic peptide that is highly effective against CRE pathogens K. pneumoniae and E. coli in vivo. In mouse septicemia models, single dose administration of MTD12813 significantly enhanced survival by promoting rapid host-mediated bacterial clearance and by modulating pathologic cytokine responses, restoring immune homeostasis, and preventing lethal septic shock. The peptide lacks direct antibacterial activity in the presence of mouse serum or in peritoneal fluid, further evidence for its indirect antibacterial mode of action. MTD12813 is highly stable in biological matrices, resistant to bacterial proteases, and nontoxic to mice at dose levels 100 times the therapeutic dose level, properties which support further development of the peptide as a first in class anti-infective therapeutic.


Asunto(s)
Antibacterianos/farmacología , Enterobacteriaceae Resistentes a los Carbapenémicos/efectos de los fármacos , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , Animales , Infecciones Bacterianas/tratamiento farmacológico , Carbapenémicos/farmacología , Citocinas/metabolismo , Diseño de Fármacos , Femenino , Humanos , Inflamación , Masculino , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Péptidos/farmacología , Fagocitosis , Sepsis/sangre
2.
Physiol Genomics ; 51(12): 657-667, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31762409

RESUMEN

Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1ß-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA.


Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Fibroblastos/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Péptidos Cíclicos/farmacología , Péptidos Cíclicos/uso terapéutico , Membrana Sinovial/metabolismo , Transcriptoma/efectos de los fármacos , alfa-Defensinas/farmacología , alfa-Defensinas/uso terapéutico , Animales , Artritis Reumatoide/inducido químicamente , Artritis Reumatoide/metabolismo , Línea Celular , Cercopithecidae , Citocinas/genética , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunosupresores/farmacología , RNA-Seq , Ratas , Sinoviocitos/metabolismo , Terpenos/farmacología , Regulación hacia Arriba
3.
Sci Rep ; 9(1): 16905, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31729441

RESUMEN

Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1ß, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.


Asunto(s)
Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Defensinas/uso terapéutico , Animales , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Candidiasis/inmunología , Candidiasis/metabolismo , Defensinas/farmacocinética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Farmacorresistencia Fúngica Múltiple/efectos de los fármacos , Femenino , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Macaca mulatta/inmunología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Análisis de Supervivencia
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