RESUMEN
Human infections with A/Jiangxi-Donghu/346/2013 (H10N8) virus have raised concerns about its pandemic potential. In order to develop a vaccine against this virus, the immunogenicity of its haemagglutinin protein was evaluated in mice. Using both whole-virion and recombinant subunit protein vaccines, we showed that two doses of either vaccine elicited neutralizing antibody responses. The protective efficacy of the vaccine-induced responses was assessed using a reverse-genetics-derived H10 reassortant virus on the A/Puerto Rico/8/34 (H1N1) backbone. The reassortant virus replicated efficiently in the respiratory tract of unvaccinated mice whereas vaccinated mice were completely protected from challenge, with no detectable viral load in the lower respiratory tract. Finally, the serum neutralizing antibody responses elicited by the H10 vaccines also exhibited cross-neutralizing activity against three heterologous wild-type H10 viruses. Collectively, these findings demonstrate that different vaccine platforms presenting the H10 haemagglutinin protein induce protective immunity.
Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Inmunogenicidad Vacunal , Subtipo H10N8 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Infecciones por Orthomyxoviridae/sangre , Animales , Reacciones Cruzadas , Perros , Células HEK293 , Glicoproteínas Hemaglutininas del Virus de la Influenza/genética , Humanos , Subtipo H10N8 del Virus de la Influenza A/genética , Subtipo H10N8 del Virus de la Influenza A/fisiología , Subtipo H1N1 del Virus de la Influenza A/genética , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/genética , Gripe Humana/sangre , Gripe Humana/inmunología , Gripe Humana/prevención & control , Células de Riñón Canino Madin Darby , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Virus Reordenados/genética , Virus Reordenados/inmunología , Sistema Respiratorio/virología , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Replicación ViralRESUMEN
New efficient antifungal agents are urgently needed to treat drug-resistant fungal infections. Here, we designed and synthesized a series of cationic xanthone amphiphilics as antifungal agents from natural α-mangostin to combat fungal resistance. The attachment of cationic residues on the xanthone scaffold of α-mangostin resulted in interesting antifungal agents with a novel mode of action. Two lead compounds (1 and 2) showed potent antifungal activity against a wide range of fungal pathogens, including drug-resistant Candida albicans, Aspergillus, and Fusarium strains and low cytotoxicity and hemolytic activity against mammalian cells. Both compounds can kill fungus rapidly by directly disrupting fungal cell membranes and avoid developing drug resistance. Additionally, compound 1 exhibited potent in vivo antifungal activity in the murine model of fungal keratitis. To our knowledge, membrane-targeting xanthone-based antifungals have not been reported previously. These results demonstrated that compounds 1 and 2 may be promising candidates for treating drug-resistant fungal infections.
Asunto(s)
Antifúngicos/química , Antifúngicos/farmacología , Farmacorresistencia Fúngica/efectos de los fármacos , Xantonas/química , Animales , Antifúngicos/síntesis química , Aspergillus/efectos de los fármacos , Candida/efectos de los fármacos , Línea Celular , Evaluación Preclínica de Medicamentos/métodos , Fibroblastos/efectos de los fármacos , Fusarium/efectos de los fármacos , Hemolíticos/química , Hemolíticos/farmacología , Humanos , Concentración 50 Inhibidora , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Ratones Endogámicos C57BL , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
A new series of semisynthetic flavone-based small molecules mimicking antimicrobial peptides has been designed from natural icaritin to combat drug-resistant Gram-positive bacterial infections. Compound 6 containing two arginine residues exhibited excellent antibacterial activity against Gram-positive bacteria, including MRSA, and very low toxicity to mammalian cells, resulting in a high selectivity of more than 511, comparable to that of several membrane-active antibiotics in clinical trials. Our data show for the first time that icaritin derivatives effectively kill bacteria. Meanwhile, this is the first study deploying a biomimicking strategy to design potent flavone-based membrane targeting antimicrobials. 6 showed rapid bactericidal activity by disrupting the bacterial membrane and can circumvent the development of bacterial resistance. Importantly, 6 was highly efficacious in a mouse model of corneal infection caused by MRSA and Staphylococcus aureus.