RESUMO
The development of effective agents for cancer therapy and inhibition of bacterial infection has drawn a great deal of interest. Photothermal therapy has been widely used for the thermal ablation of tumor cells. In addition, antibiotics have the ability to inhibit the growth of bacteria. Thus, the combination of photothermal therapy and antibiotics may be one of the methods to address the problem. Herein, it is the first time that daptomycin (Dap) micelles were used as the template and reducing agents to prepare stable daptomycin-gold nanoflowers (Dap-AunNFs) under mild conditions. The energy dispersive spectrometer (EDS) spectrum and X-ray diffraction (XRD) spectrum indicated that Dap-AunNFs were successfully prepared. When the molar ratio of HAuCl4 to Dap was 6, the gold nanoparticles inside of Dap-AunNFs were about 80 nm with flower-like shape. In addition, the photothermal conversion efficiency of Dap-Au6NFs was about 40%. More importantly, Dap-Au6NFs inhibited the growth of tumors and bacteria under the radiation of near-infrared light at 808 nm. The prepared Dap-Au6NFs could be used as photothermal antitumor and antibacterial agents in the future.
Assuntos
Antibacterianos/química , Antineoplásicos/química , Daptomicina/química , Daptomicina/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Feminino , Camundongos , Micelas , Neoplasias/tratamento farmacológico , Fototerapia/métodosRESUMO
Increased usage of daptomycin to treat infections caused by Gram-positive bacterial pathogens has resulted in emergence of resistant mutants. In a search for more effective daptomycin analogues through medicinal chemistry studies, we found that methylation at the nonproteinogenic amino acid kynurenine in daptomycin could result in significant enhancement of antibacterial activity. Termed "kynomycin," this new antibiotic exhibits higher antibacterial activity than daptomycin and is able to eradicate methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains, including daptomycin-resistant strains. The improved antimicrobial activity of kynomycin was demonstrated in in vitro time-killing assay, in vivo wax worm model, and different mouse infection models. The increased antibacterial activity, improved pharmacokinetics, and lower cytotoxicity of kynomycin, compared to daptomycin, showed the promise of the future design and development of next-generation daptomycin-based antibiotics.
Assuntos
Antibacterianos/uso terapêutico , Depsipeptídeos/uso terapêutico , Lipopeptídeos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Antibacterianos/toxicidade , Permeabilidade da Membrana Celular/efeitos dos fármacos , Daptomicina/química , Daptomicina/uso terapêutico , Depsipeptídeos/síntese química , Depsipeptídeos/farmacocinética , Depsipeptídeos/toxicidade , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterococcus/efeitos dos fármacos , Feminino , Células HEK293 , Humanos , Lepidópteros/efeitos dos fármacos , Lepidópteros/microbiologia , Lipopeptídeos/síntese química , Lipopeptídeos/farmacocinética , Lipopeptídeos/toxicidade , Masculino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Metilação , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Testes de Sensibilidade MicrobianaRESUMO
In order to improve the stability of AgNPs and decrease the dosage of Daptomycin for killing bacteria, a reduced graphene oxide (rGO) was used for simultaneously anchoring AgNPs and Daptomycin to prepare rGO@Ag@Dap nanocomposites. In vitro experiments showed that the nanocomposites can efficiently kill four kinds of pathogenic bacteria, especially two kinds of Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) through damaging cell integrity, producing ROS, decreasing ATP and GSH and disrupting bacterial metabolism. Against Gram-positive bacteria, the rGO@Ag@Dap nanocomposites showed a cooperative antibacterial effect. Moreover, in vivo experiments showed that rGO@Ag@Dap can improve the healing of wounds infected with bacteria by efficiently killing the bacteria on the wounds and further promoting skin regeneration and dense collagen deposition. In summary, the above results suggest that the cooperative function of AgNPs with Daptomycin can significantly improve antibacterial efficiency against infectious diseases caused by bacteria, especially for therapies made ineffective due to the drug resistance of pathogenic bacteria.
Assuntos
Daptomicina/administração & dosagem , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Grafite/química , Prata/administração & dosagem , Animais , Bacillus subtilis/efeitos dos fármacos , Daptomicina/química , Daptomicina/farmacologia , Modelos Animais de Doenças , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Nanocompostos/química , Prata/química , Prata/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Cicatrização/efeitos dos fármacosRESUMO
CONTEXT: Chitosan nanoparticles were prepared to encapsulate daptomycin and proposed as a delivery system of this antibiotic to the eye for the treatment of bacterial endophthalmitis. OBJECTIVE: The aim of this study was to develop daptomycin-loaded nanoparticles to apply directly to the eye, as a possible non-invasive and less painful alternative for the treatment of endophthalmitis, increasing the effectiveness of treatment and reducing toxicity associated with systemic administration. MATERIALS AND METHODS: Nanoparticles were obtained by ionotropic gelation between chitosan and sodium tripolyphosphate (TPP). Physicochemical and morphological characteristics of nanoparticles were evaluated, as well as determination of antimicrobial efficiency of encapsulated daptomycin and stability of the nanoparticles in the presence of lysozyme and mucin. RESULTS: Loaded nanoparticles presented mean particle sizes around 200 nm, low polydispersity index, and positive zeta potential. Morphological examination by scanning electron microscopy (SEM) confirmed their small size and round-shaped structure. Encapsulation efficiency ranged from 80 to 97%. Total in vitro release of daptomycin was obtained within 4 h. Determination of minimum inhibitory concentrations (MICs) showed that bacteria were still susceptible to daptomycin encapsulated into the nanoparticles. Incubation with lysozyme did not significantly affect the integrity of the nanoparticles, although mucin positively affected their mucoadhesive properties. DISCUSSION AND CONCLUSION: The obtained nanoparticles have suitable characteristics for ocular applications, arising as a promising solution for the topical administration of daptomycin to the eye.
Assuntos
Antibacterianos/administração & dosagem , Quitosana/química , Daptomicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Administração Oftálmica , Antibacterianos/química , Química Farmacêutica/métodos , Daptomicina/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Endoftalmite/tratamento farmacológico , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Nanopartículas , Tamanho da Partícula , Polifosfatos/químicaRESUMO
The aggregation behavior and critical aggregation concentration (CAC) values of daptomycin in aqueous solutions were evaluated under the external factors of pH, temperature, daptomycin concentration, and calcium ions concentration by using the complementary characterization techniques, fluorescence, dynamic and static light scattering, and nuclear magnetic resonance (NMR) spectroscopy. On the basis of the intrinsic fluorescence resonance energy transfer of daptomycin, the CAC values were identified by an upward inflection of the fluorescence emission from Kyn-13 at 460 nm. The pH-dependent CAC values were determined to be 0.14 mM at pH 3.0, 0.12 mM at pH 4.0, and 0.20 mM at pH 2.5 and 5.0. The CAC values obtained by fluorescence spectroscopy were confirmed by dynamic light scattering and NMR spectroscopy.
Assuntos
Antibacterianos/química , Daptomicina/química , Ionóforos/química , Antibacterianos/metabolismo , Sinalização do Cálcio , Daptomicina/metabolismo , Estabilidade de Medicamentos , Transferência Ressonante de Energia de Fluorescência , Temperatura Alta , Concentração de Íons de Hidrogênio , Ionóforos/metabolismo , Cinética , Ácido Cinurênico/química , Cinurenina/química , Cinurenina/metabolismo , Nefelometria e Turbidimetria , Ressonância Magnética Nuclear Biomolecular , Concentração Osmolar , Tamanho da Partícula , Estabilidade Proteica , Solubilidade , Espectrofotometria Ultravioleta , Triptofano/químicaRESUMO
Introducción. Los Staphylococcus coagulasa negativos(SCN) se han convertido en uno de los patógenos nosocomialesmás frecuentes y con una elevada tasa de mortalidad, debido ala mayor supervivencia de enfermos graves, estados deinmunosupresión prolongados y presencia de materialesextraños, como catéteres, prótesis, marcapasos, etc. Además,existe un importante aumento en las resistencias frente a losantimicrobianos, sobre todo betalactámicos, y se hadocumentado cómo el incremento en la CMI para vancomicinaconlleva una pérdida de su eficacia clínica, por lo que se buscannuevas alternativas terapéuticas, como daptomicina.El objetivo de este trabajo es estudiar la actividad dedaptomicina, ciprofloxacino, clindamicina y cotrimoxazol endos grupos de SCN clínicamente significativos, uno con CMI90para vancomicina ≤ 1 mg/L y el otro con CMI90 de 2 mg/L.Métodos. Se identificaron y estudiaron las CMI90 paraciprofloxacino, clindamicina y cotrimoxazol de 54 cepas de SCNclínicamente significativos mediante los paneles combo 22 deMicroScan (Dade behring, Siemens). La CMI90 para daptomicinase realizó mediante Etest (AB BioMèrieux, Solna, Suecia) enplacas de Mueller Hinton (BioMèrieux, Francia).Resultados. En el Grupo I (CMI90 para vancomicina ≤ 1mg/L) se estudiaron 19 cepas y en el Grupo II (CMI90 paravancomicina = 2 mg/L) se estudiaron 35 cepas. Expresadas enmg/L, los rangos de CMI90 para daptomicina fueron 0.047-0.5en el Grupo I y 0,064-0,5 en el Grupo II. Para ciprofloxacinohubo 8 cepas sensibles y 11 resistentes en el Grupo I y 10sensibles y 25 resistentes en el Grupo II. Para clindamicina hubo7 cepas sensibles y 12 resistentes en el Grupo I y 16 sensibles y19 resistentes en el Grupo II. Finalmente, Para cotrimoxazolhubo 10 cepas sensibles y 9 resistentes en el Grupo I y 19sensibles y 16 resistentes en el Grupo II...(AU)
Introduction. Coagulase Negative Staphylococci (CNS)have become one of the most common nosocomial pathogensand it has a high mortality rate due to the increased ofseriously ill patients survival, long states immunosuppressionand presence of foreign bodies, such as catheters, prostheses,pacemakers, etc. In addition, there is a significant increase inresistance to antimicrobial drugs, especially beta-lactams, andthe increase in the MIC for vancomycin leads to a loss ofclinical efficacy. This necessitates the search for newtherapeutic alternatives, such as daptomycin.The aim of this paper is to study the activity ofdaptomycin, ciprofloxacin, clindamycin and cotrimoxazole intwo groups of clinically significant CNS. a MIC90 withvancomycin ≤ 1 mg/L and the other with MIC90 2 mg/L.Methods. We identified and studied MIC90 tociprofloxacin, clindamycin and cotrimoxazole from 54 strainsof clinically significant by the CNS Combo 22 Microscan panels(Dade Behring, Siemens). The MIC90 for daptomycin wasperformed using Etest (AB BioMérieux, Solna, Sweden) onMueller Hinton plates (BioMérieux, France).Results In Group I (vancomycin MIC90 ≤ 1 mg/L) were 19 strains whereas in Group II (vancomycin MIC90 = 2 mg/L) were35 strains. Expressed in mg/L, MIC90 ranges for daptomycinwere 0.047-0.5 in Group I and 0.064-0.5 in Group II. Forciprofloxacin were 8 sensitive strains and 11 resistant in GroupI and 10 sensitive and 25 resistant in Group II. For clindamycinwere 7 sensitive strains and 12 resistant in Group I and 16sensitive and 19 resistant in Group II. Finally, for cotrimoxazolewere 10 sensitive strains and 9 resistant in Group I and 19sensitive and 16 resistant in Group II...(AU)
Assuntos
Humanos , Masculino , Feminino , Sensibilidade e Especificidade , Vancomicina/uso terapêutico , Daptomicina/uso terapêutico , Ciprofloxacina/uso terapêutico , Clindamicina/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Vancomicina/química , Vancomicina/farmacologia , Daptomicina/química , Daptomicina/farmacologia , Daptomicina/farmacocinética , Ciprofloxacina/farmacologia , Ciprofloxacina/farmacocinética , Clindamicina/farmacologia , Clindamicina/farmacocinética , Terapia de Imunossupressão/métodosRESUMO
Daptomycin is a lipopeptide antibiotic that exhibits bactericidal activity against a range of Gram-positive bacterial pathogens including strains resistant to other antibiotics, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. Daptomycin is licensed both in the USA and Europe for the treatment of complicated skin and skin-structure infections and in the USA this has recently been expanded to include bacteremia and right-sided endocarditis due to Staphylococcus aureus. A marketing authorization application for this indication is currently under consideration by the European Medicines Agency. The pharmacokinetic and pharmacodynamic properties of daptomycin allow for once-daily dosing, although it is recommended that the dosing interval be increased to 2 days in patients with renal impairment. Clinical data generally indicate that daptomycin is well tolerated, but nonetheless concerns persist regarding potential muscle toxicity. Emergence of resistance to daptomycin has been reported, highlighting the need for prospective surveillance to determine the extent of this potential problem.
Assuntos
Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Bactérias Gram-Positivas/efeitos dos fármacos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Ensaios Clínicos como Assunto , Daptomicina/química , Daptomicina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Endocardite/tratamento farmacológico , Endocardite/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Estrutura Molecular , Coelhos , Ratos , Ratos Wistar , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Dermatopatias Bacterianas/tratamento farmacológico , Resultado do TratamentoRESUMO
Daptomycin is a novel cyclic lipopeptide antibiotic that provides rapid bactericidal activity against gram-positive pathogens in vitro, including methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, vancomycin-resistant S. aureus, penicillin-resistant Streptococcus pneumoniae, and ampicillin- and vancomycin-resistant enterococci. The United States Food and Drug Administration recently approved daptomycin for treatment of complicated skin and skin-structure infections. Its efficacy in the treatment of more-serious infections (e.g., staphylococcal bacteremia) is under investigation. As an intravenous agent that is administered once per day, it offers a convenient regimen for therapy that is continued after discharge, with a side effect profile that appears minimal and manageable. Spontaneous acquisition of resistance in vitro is rare, and hopefully this characteristic will extrapolate into the clinical setting. The rapid bactericidal activity, low potential for resistance, and promising safety profile associated with this agent will make it a useful addition to our growing armamentarium of antibiotics active against gram-positive pathogens.