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1.
Int J Nanomedicine ; 14: 7975-7985, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632012

RESUMO

Background: Multidrug-resistant bacteria such as extended-spectrum beta-lactamase (ESBL), Enterobacteriaceae, and methicillin-resistant Staphylococcus aureus (MRSA) pose a challenge to the human health care system. MRSA is among the major causes of hospital-acquired and community infections. Methods: Therefore, in the present study, we evaluated the antibacterial activity of silver nanoparticles synthesized by Fusarium oxysporum (AgNPbio) in combination with simvastatin against reference and multidrug-resistant bacterial strains. Results: Simvastatin showed a minimal inhibitory concentration (MIC) ranging from 0.062 to 0.25 mg mL-1 against MRSA. AgNPbio with a size of 77.68± 33.95 nm and zeta potential -34.6 ± 12.7 mV showed an MIC of 0.212 mg mL-1 against S. aureus including MRSA strains. The checkerboard assay and time-kill curves exhibited a synergistic effect of the simvastatin-AgNPbio combination on antibacterial activity against MRSA strains. The combination of simvastatin and AgNPbio demonstrated antibacterial activity against Escherichia coli producing ESBL. Scanning electron microscopy showed the formation of cell surface protrusions after treatment with AgNPbio and the formation of a large amorphous mass after treatment with simvastatin, both in MRSA. Conclusion: Our results indicate that the combination of AgNPbio and simvastatin could be a great future alternative in the control of bacterial infections, where, when combined with simvastatin, smaller doses of AgNPbio are required, with the same antibacterial activity.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Fusarium/metabolismo , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Prata/farmacologia , Sinvastatina/farmacologia , Morte Celular/efeitos dos fármacos , Sinergismo Farmacológico , Eritrócitos/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Fusarium/ultraestrutura , Humanos , Nanopartículas Metálicas/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana
2.
Appl Biochem Biotechnol ; 189(4): 1291-1303, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31254228

RESUMO

With growing concern about the possible risks and side effects of antibiotic drugs, more and more natural products with antibacterial activity are studied as the substitutes. In this paper, the antibacterial activity of hydroquinone and arbutin in Ainsliaea bonatii was investigated, which both displayed relatively strong antibacterial activity against Staphylococcus aureus (SA), methicillin-resistant S. aureus (MRSA), and extended spectrum ß-lactamase S. aureus (ESBL-SA). The antibacterial mechanism of hydroquinone had been explored by scanning electron microscopy (SEM), alkaline phosphatase (AKP), and bacterial extracellular protein leakage. Results showed that hydroquinone could destroy the bacterial cell wall and membrane, increase permeability, lead leakage of intracellular substance affect synthesis of protein, and influence expression of genes.


Assuntos
Antibacterianos/farmacologia , Arbutina/farmacologia , Hidroquinonas/farmacologia , Lamiaceae/química , Staphylococcus aureus Resistente à Meticilina/metabolismo , Antibacterianos/química , Arbutina/química , Hidroquinonas/química , Staphylococcus aureus Resistente à Meticilina/ultraestrutura
3.
J Med Microbiol ; 68(8): 1129-1136, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241446

RESUMO

PURPOSE: Staphylococcus aureus causes a wide range of infections, such as endocarditis, pneumonia, osteomyelitis, skin and soft tissue infections, and implant/in-dwelling device-related infections. S. aureus poses a significant challenge to clinicians because of its ability to rapidly acquire multi-drug resistance and quickly progress into a recurrent, chronic infection by biofilm formation. Levonadifloxacin (WCK 771) is a novel broad-spectrum antibacterial agent (it recently completed a phase 3 trial in India) with a differentiated mechanism of action involving high affinity to staphylococcal DNA gyrase, and is active against multi-drug-resistant (MDR) S. aureus, including those that are resistant to quinolones. The present study investigated the bactericidal activity of levonadifloxacin against biofilm-embedded S. aureus clinical isolates in comparison with other anti-S. aureus drugs. METHODOLOGY: The bactericidal activity of levonadifloxacin and comparator drugs such as vancomycin, linezolid and daptomycin was evaluated against planktonic and biofilm-encapsulated recent methicillin- and quinolone-resistant S. aureus clinical isolates using time-kill, biofilm eradication and scanning electron microscopy analysis. RESULTS: Levonadifloxacin displayed a consistent ≥90 % bacterial kill rate against biofilm-embedded organisms, while vancomycin and linezolid displayed variable activity and daptomycin did not show any activity. Scanning electron microscopy images further confirmed the efficacy of levonadifloxacin against biofilm, showing the disruption of biofilm structure and a corresponding reduction in the viable bacterial count. CONCLUSION: These results show that levonadifloxacin has an improved bactericidal effect on biofilm-embedded quinolone-resistant S. aureus and meticillin-resistant S. aureus, and that it can be a promising treatment option for such infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Humanos , Meticilina/farmacologia , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/fisiologia , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Quinolonas/farmacologia , Infecções Estafilocócicas/microbiologia , Fatores de Tempo
4.
ACS Appl Mater Interfaces ; 11(21): 18907-18913, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31062953

RESUMO

Tackling microbial infection associated with biomaterial surfaces has been an urgent need. Synthetic ß-peptide polymers can mimic host defense peptides and have potent antimicrobial activities without driving the bacteria to develop antimicrobial resistance. Herein, we demonstrate a plasma surface activation-based practical ß-peptide polymer modification to prepare antimicrobial surfaces for biomedical materials such as thermoplastic polyurethane (TPU), polytetrafluoroethylene, polyvinyl pyrrolidone, polyvinyl chloride, and polydimethylsiloxane. The ß-peptide polymer-modified surfaces demonstrated effective killing on drug-resistant Gram-positive and Gram-negative bacteria. The antibacterial function retained completely even after the ß-peptide polymer-modified surfaces were stored at ambient temperature for at least 2 months. Moreover, the optimum ß-peptide polymer (50:50 DM-Hex)-modified surfaces displayed no hemolysis and cytotoxicity. In vivo study using methicillin-resistant Staphylococcus aureus (MRSA)-pre-incubated TPU-50:50 DM-Hex surfaces for subcutaneous implantation revealed a 3.4-log reduction of MRSA cells after the implantation for 11 days at the surrounding tissue of implanted TPU sheet and significant suppression of infection, compared to bare TPU control. These results imply promising and practical applications of ß-peptide polymer tethering to prepare infection-resistant surfaces for biomedical materials and devices.


Assuntos
Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Materiais Biocompatíveis/farmacologia , Animais , Peptídeos Catiônicos Antimicrobianos/farmacologia , Infecções Bacterianas/microbiologia , Escherichia coli/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Teste de Materiais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos , Testes de Sensibilidade Microbiana , Miócitos de Músculo Liso/efeitos dos fármacos , Células NIH 3T3 , Poliuretanos/farmacologia , Ratos
5.
Int J Nanomedicine ; 14: 2903-2914, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31114199

RESUMO

Background: Titanium (Ti) implant-associated infection, which is mostly caused by bacterial adhesion and biofilm formation, may result in implant failure and secondary surgery. Thus it is an urgent issue to prevent bacterial infections at the earliest step. Purpose: To develop a novel surface strategy of polydopamine (PDA) and silver (Ag) nanoparticle-loaded TiO2 nanorods (NRDs) coatings on Ti alloy. Materials and methods: Ag-TiO2@PDA NRDs was fabricated on Ti alloy by hydrothermal synthesis. The antibacterial activity of Ag-TiO2@PDA NRDs against Escherichia coli and methicillin-resistant Staphylococcus aureus were tested by FE-SEM, Live/Dead staining, zone of inhibition, bacteria counting method and protein leakage analysis in vitro. In addition, an implant infection model was conducted and the samples were tested by X-ray, Micro-CT and histological analysis in vivo. Besides, cell morphology and cytotoxicity of Mouse calvarial cells (MC3T3-E1) were characterized by FE-SEM, immunofluorescence and CCK-8 test in vitro. Results: Our study successfully developed a new surface coating of Ag-TiO2@PDA NRDs. The selective physical puncture of bacteria and controlled release of Ag+ ions of Ag-TiO2@PDA NRDs achieved a long-lasting bactericidal ability and anti-biofilm activity with satisfied biocompatibility. Conclusion: This strategy may be promising for clinical applications to reduce the occurrence of infection in the implant surgeries.


Assuntos
Antibacterianos/farmacologia , Indóis/química , Nanopartículas Metálicas/química , Nanotubos/química , Polímeros/química , Prata/farmacologia , Titânio/química , Animais , Aderência Bacteriana/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Forma Celular/efeitos dos fármacos , Preparações de Ação Retardada/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/ultraestrutura , Íons , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos , Testes de Sensibilidade Microbiana , Nanotubos/ultraestrutura , Infecções Relacionadas à Prótese/microbiologia , Infecções Relacionadas à Prótese/patologia , Propriedades de Superfície
6.
Int J Nanomedicine ; 14: 2171-2190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988615

RESUMO

Background and aim: Bimetallic silver/gold nanosystems are expected to significantly improve therapeutic efficacy compared to their monometallic counterparts by maintaining the general biocompatibility of gold nanoparticles (AuNPs) while, at the same time, decreasing the relatively high toxicity of silver nanoparticles (AgNPs) toward healthy human cells. Thus, the aim of this research was to establish a highly reproducible one-pot green synthesis of colloidal AuNPs and bimetallic Ag/Au alloy nanoparticles (NPs; Ag/AuNPs) using starch as reducing and capping agent. Methods: The optical properties, high reproducibility, stability and particle size distribution of the colloidal NPs were analyzed by ultraviolet (UV)-visible spectroscopy, dynamic light scattering (DLS) and ζ-potential. The presence of starch as capping agent was determined by Fourier transform infrared (FT-IR) spectroscopy. The structural properties were studied by X-ray diffraction (XRD). Transmission electron microscopy (TEM) imaging was done to determine the morphology and size of the nanostructures. The chemical composition of the nanomaterials was determined by energy-dispersive X-ray spectroscopy (EDS) and inductively coupled plasma mass spectrometry (ICP-MS) analysis. To further study the biomedical applications of the synthesized nanostructures, antibacterial studies against multidrug-resistant (MDR) Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) were conducted. In addition, the NPs were added to the growth media of human dermal fibroblast (HDF) and human melanoma cells to show their cytocompatibility and cytotoxicity, respectively, over a 3-day experiment. Results: UV-visible spectroscopy confirmed the highly reproducible green synthesis of colloidal AuNPs and Ag/AuNPs. The NPs showed a face-centered cubic crystal structure and an icosahedral shape with mean particle sizes of 28.5 and 9.7 nm for AuNPs and Ag/AuNPs, respectively. The antibacterial studies of the NPs against antibiotic-resistant bacterial strains presented a dose-dependent antimicrobial behavior. Furthermore, the NPs showed cytocompat-ibility towards HDF, but a dose-dependent anticancer effect was found when human melanoma cells were grown in presence of different NP concentrations for 72 hours. Conclusion: In this study, mono- and bimetallic NPs were synthesized for the first time using a highly reproducible, environmentally friendly, cost-effective and quick method and were successfully characterized and tested for several anti-infection and anticancer biomedical applications.


Assuntos
Antibacterianos/farmacologia , Ouro/química , Nanopartículas Metálicas/química , Prata/química , Amido/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Coloides/síntese química , Coloides/química , Contagem de Colônia Microbiana , Difusão Dinâmica da Luz , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/ultraestrutura , Fibroblastos/efeitos dos fármacos , Humanos , Hidrodinâmica , Nanopartículas Metálicas/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Reprodutibilidade dos Testes , Espectrometria por Raios X , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Eletricidade Estática , Difração de Raios X
7.
Mar Biotechnol (NY) ; 21(1): 88-98, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30612218

RESUMO

Bacterial biofilm can cause nosocomial recurrent infections and implanted device secondary infections in patients and strongly promotes development of pathogenic drug resistance in clinical treatments. Butenolide is an effective anti-macrofouling compound derived from a marine Streptomyces sp., but its antibiofilm efficacy remains largely unexplored. In the present study, the antibiofilm activities of butenolide were examined using biofilms formed by both Gram-positive and Gram-negative pathogenic model species. Four Escherichia coli strains, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus (MRSA) were used as targets in antibiofilm assays that examined the effects of butenolide, including the following: (i) on bacterial growth; (ii) in inhibiting biofilm formation and eradicating mature biofilm; (iii) on biofilm structures. In addition, the synergistic effect between butenolide with tetracycline was also examined. Butenolide not only effectively inhibited the biofilm formation but also eradicated pre-formed biofilms of tested bacteria. Fractional inhibitory concentration index (FICI) indicated that butenolide was a potential tetracycline enhancer against E. coli, P. aeruginosa, and MRSA. These results indicated that butenolide may hold a great potential as an effective antibiofilm agent to control and prevent biofilm-associated infections in future clinical treatments.


Assuntos
4-Butirolactona/análogos & derivados , Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , 4-Butirolactona/farmacologia , Biofilmes/crescimento & desenvolvimento , Combinação de Medicamentos , Sinergismo Farmacológico , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/ultraestrutura , Tetraciclina/farmacologia
8.
Microb Pathog ; 127: 106-115, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30503959

RESUMO

The synthesized potent piperazine analog ChDiPiCa was characterised by various spectroscopic techniques and for the first time evaluated functional membrane microdomain (FMM) disassembly in methicillin-resistant Staphylococcus aureus (MRSA). The ChDiPiCa showed excellent in vitro biocidal activity against MRSA at 26 µg/mL compared to the antibiotic streptomycin and bacitracin 14 µg/mL and 13 µg/mL at 10 µg concentration respectively. The membrane damaging property was confirmed by the SEM analysis. Further, we addressed the new approach for the first time to overcome antibiotic resistance of MRSA through membrane microdomain miss loading to lipids. By which, the ChDiPiCa confirms the significant activity in miss loading of FMM of MRSA which is validated by the fatty acid profile and lipid analysis. The result shows that, altered saturated (Lauric acid and Myristic acid), mono unsaturated (Oleic acid), and poly unsaturated (Linoleic acid and Linolenic acid) fatty acids and hypothesises, altered the membrane functional lipids. For the better understanding of miss loading of FMM by the ChDiPiCa, the in-silico molecular docking studies was analyzed and confirmed the predicted role. This suggests the way to develop ChDiPiCa in medicinal chemistry as anti-MRSA candidates and also this report opens up new window to treat microbial pathogens and infections.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Microdomínios da Membrana/efeitos dos fármacos , Microdomínios da Membrana/metabolismo , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/metabolismo , Piperazina/farmacologia , Antibacterianos/síntese química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Metabolismo dos Lipídeos/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Piperazina/análogos & derivados , Piperazina/síntese química
9.
Gastrointest Endosc ; 89(1): 105-114, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30120959

RESUMO

BACKGROUND AND AIMS: It has been increasingly recognized that the safety of GI endoscopes needs to be improved by addressing the small margin of safety of high-level disinfectants (HLDs) and the failure of HLDs to clear multidrug-resistant organisms and biofilms. There is also an unmet need for effective low-temperature sterilization techniques that have a clear pathway for U.S. Food and Drug Administration clearance. Here, we report the results of our investigation of a novel argon plasma-activated gas (PAG) for disinfection and potentially sterilization of biofilm-contaminated endoscopic channels. METHODS: Test polytetrafluoroethylene channel segments were contaminated with 4-, 24- and 48-hour luminal biofilms of methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, or Escherichia coli and were treated by PAG flowing for up to 9 minutes. After PAG treatment, inactivation and dispersal of luminal bacterial biofilms and their regrowth in 48 hours were evaluated. Reactive species induced by PAG were measured with colorimetric probes and electron spin resonance spectrometry. Surface morphology and elemental composition of PAG-treated channel material were analyzed with scanning electron microscopy. RESULTS: PAG treatment for 9 minutes led to more than 8 log reduction of viable cells and dispersal of 24- and 48-hour luminal biofilms of all 3 bacteria and to suppression of their regrowth, whereas it resulted in little morphologic abnormalities in channel material. Ozone concentration of PAG fell to below .01 ppm within 30 seconds of switching off the plasma. PAG-treated deionized water was acidified with numerous types of reactive species, each with a concentration some 3 orders of magnitude or more below its bacterial inhibition concentration. CONCLUSIONS: PAG is capable of effectively and rapidly disinfecting luminal bacterial biofilms and offers an alternative to the step of HLDs and/or ethylene oxide in the endoscope reprocessing procedure with safety to personnel and environment.


Assuntos
Argônio/farmacologia , Biofilmes/efeitos dos fármacos , Endoscópios Gastrointestinais/microbiologia , Contaminação de Equipamentos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Desinfecção/métodos , Espectroscopia de Ressonância de Spin Eletrônica , Escherichia coli/ultraestrutura , Humanos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Microscopia Eletrônica de Varredura , Pseudomonas aeruginosa/ultraestrutura , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Eur J Pharm Sci ; 127: 208-216, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30412770

RESUMO

The increasing drug-resistance pathogens among gram-positive bacterial species are becoming a major health concern nowadays. Over the past few years, the bactericidal efficacy of nano­silver against some drug-resistant gram-positive bacteria has been established, however further investigation is needed to determine whether nano­silver could be an option for the treatment of drug-resistant gram-positive microbial infections. The purpose of the present study was to determine the bactericidal efficacy of nano­silver with its membrane destroying property using drug-resistant Staphylococcus aureus MTCC 3160. In the present study, bactericidal assessment of nano­silver with different antibiotics was determined by agar well diffusion method. Interaction of nano­silver towards bacterial membrane was carried to understand the probable bactericidal actions of nano­silver, which was further confirmed by respiratory chain dehydrogenase, zeta potential, Scanning Electron Microscopy (SEM) and Gas Chromatography-Mass Spectrometry (GC-MS). The effect of nano­silver on bacterial Deoxyribonucleic Acids (DNA) was evaluated by agarose gel electrophoresis. Bactericidal assessment of nano­silver showed a very strong bactericidal action compare to antibiotics. The binding affinity of nano­silver towards bacterial membrane induced loss of catalytic activity for respiratory chain dehydrogenases. Zeta potential, SEM and GC-MS analysis also revealed extensive damage to the bacterial cell membrane. Moreover, the analysis of agarose gel electrophoresis revealed that nano­silver can enhance the decomposability of bacterial DNA, which was directly attached to the bacterial cell membrane. The present findings suggested that nano­silver directly interact with the bacterial cell surface without the need to penetrate; and this distinctive property raises the hope that nano­silver will remain an important bactericide in bacteria than antibiotics.


Assuntos
Antibacterianos/administração & dosagem , Permeabilidade da Membrana Celular/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Nanopartículas/administração & dosagem , Prata/administração & dosagem , Proteínas de Bactérias/metabolismo , DNA Bacteriano/metabolismo , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Microscopia Eletrônica de Varredura
11.
Yakugaku Zasshi ; 138(12): 1537-1547, 2018.
Artigo em Japonês | MEDLINE | ID: mdl-30504670

RESUMO

We previously showed that a naturally occurring macrocyclic bis(bibenzyl) derivative, riccardin C (RC), exhibits antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA), with a potency comparable to that of the clinically used drug vancomycin. Here, we synthesized a series of RC derivatives to explore the structure-activity relationships (SAR). The SAR results clearly indicated that the number and positions of the phenolic hydroxyl groups are primary determinants of the anti-MRSA activity. Pharmacological characterization of the macrocyclic bis(bibenzyl) derivatives, together with fragment compounds and their dimers, indicated that the macrocycles and the fragment compounds elicit anti-MRSA activity with different mechanism(s) of action. The macrocyclic bis(bibenzyl)s are bactericidal, while the fragment compounds are bacteriostatic, showing only weak bactericidal activity. Treatment with a macrocyclic bis(bibenzyl) derivative significantly changed the intracellular Na+ and K+ concentrations of Staphylococcus aureus, and transmission electron microscopy revealed that treated cells developed intracellular lamellar mesosomal-like structures. These results indicated that the macrocyclic compound directly damages the gram-positive bacterial membrane, resulting in increased permeability.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Desenho de Fármacos , Éteres Cíclicos/síntese química , Éteres Cíclicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Farmacorresistência Bacteriana , Éteres Cíclicos/química , Staphylococcus aureus Resistente à Meticilina/citologia , Staphylococcus aureus Resistente à Meticilina/metabolismo , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Microscopia Eletrônica de Transmissão , Potássio/metabolismo , Sódio/metabolismo , Relação Estrutura-Atividade
12.
Molecules ; 23(12)2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30513653

RESUMO

The well-known and rapidly growing phenomenon of bacterial resistance to antibiotics is caused by uncontrolled, excessive and inappropriate use of antibiotics. One of alternatives to antibiotics is Photodynamic Antibacterial Chemotherapy (PACT). In the present study, the effect of PACT using a photosensitizer Rose Bengal alone and in combination with antibiotics including methicillin and derivatives of sulfanilamide synthesized by us was tested against antibiotic-sensitive and antibiotic-resistant clinical isolates of Gram-positive S. aureus and Gram-negative P. aeruginosa. Antibiotic-sensitive and resistant strains of P. aeruginosa were eradicated by Rose Bengal under illumination and by sulfanilamide but were not inhibited by new sulfanilamide derivatives. No increase in sensitivity of P. aeruginosa cells to sulfanilamide was observed upon a combination of Rose Bengal and sulfanilamide under illumination. All tested S. aureus strains (MSSA and MRSA) were effectively inhibited by PACT. When treated with sub-MIC concentrations of Rose Bengal under illumination, the minimum inhibitory concentrations (MIC) of methicillin decreased significantly for MSSA and MRSA strains. In some cases, antibiotic sensitivity of resistant strains can be restored by combining antibiotics with PACT.


Assuntos
Antibacterianos/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/isolamento & purificação , Staphylococcus aureus/isolamento & purificação , Sulfanilamida/farmacologia
13.
Int J Nanomedicine ; 13: 4987-5002, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30214202

RESUMO

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most predominant and fatal pathogens at wound infection sites. MRSA is difficult to treat because of its antibiotic resistance and ability to form biofilms at the wound site. Methods: In this study, a novel nanoscale liquid film-forming system (LFFS) loaded with benzalkonium bromide was produced based on polyvinyl alcohol and chitosan. Results: This LFFS showed a faster and more potent effect against MRSA252 than benzalkonium bromide aqueous solution both in vitro and in vivo. Additionally, the LFFS had a stronger ability to destroy biofilms (5 mg/mL) and inhibit their formation (1.33 µg/mL). The LFFS inflicted obvious damage to the structure and integrity of MRSA cell membranes and caused increases in the release of alkaline phosphate and lactate dehydrogenase in the relative electrical conductivity and in K+ and Mg2+ concentrations due to changes in the MRSA cell membrane permeability. Conclusion: The novel LFFS is promising as an effective system for disinfectant delivery and for application in the treatment of MRSA wound infections.


Assuntos
Antibacterianos/farmacologia , Biofilmes , Quitosana/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Nanopartículas/química , Álcool de Polivinil/química , Cicatrização/efeitos dos fármacos , Animais , Biofilmes/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Liberação Controlada de Fármacos , Feminino , Humanos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Nanopartículas/ultraestrutura
14.
Sci Rep ; 8(1): 13117, 2018 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-30177735

RESUMO

The impact of multi-drug resistant bacterial strains on human health is reaching worrisome levels. Over 2 million people are infected by resistant bacteria, and more than 700,000 people die each year because of the continuous spread of resistant strains. The development of new antibiotics and the prudent use of existing ones to prolong their lifespan require a constant effort by drug industries and healthcare workers. The re-purposing of existing drugs for use as antimicrobial agents would streamline the development of new antibacterial strategies. As part of this effort, we screened a panel of drugs previously characterized to be epigenetic modulators/pro-apoptotic/differentiative drugs. We selected a few compounds that alter Gram-positive growth. Among these, UVI5008, a derivative of the natural compound psammaplin A (Psa_A), was identified. The interaction of Psa_A with the DNA gyrase enzyme has been shown, and here, we hypothesized and confirmed the gyrase-specific activity by biochemical assays. UVI5008 exhibited growth inhibition activity against Staphylococcus aureus via structural modification of the cell wall, which was observed by SEM electron microscopy. Based on our findings, we propose UVI5008 as an alternative antibacterial compound against methicillin-resistant (Met.R) S. aureus strains.


Assuntos
Antibacterianos/farmacologia , Parede Celular/efeitos dos fármacos , DNA Girase/genética , Dissulfetos/farmacologia , Regulação Bacteriana da Expressão Gênica , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oximas/farmacologia , Parede Celular/metabolismo , Parede Celular/ultraestrutura , DNA Girase/metabolismo , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla/genética , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Ligação Proteica
15.
BMC Complement Altern Med ; 18(1): 261, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257662

RESUMO

BACKGROUND: Antimicrobial resistance was one of serious worldwide problems confused many researchers. To solve this problem, we explored the antibacterial effect of chelerythrine, a natural compound from traditional Chinese medicine and studied its action. METHODS: The contents of chelerythrine from different fractions of Toddalia asiatica (Linn) Lam (T. asiatica) were determined. The anti-bacterial activities of chelerythrine were tested by disc diffusion method (K-B method). Scanning electron microscopy (SEM), alkaline phosphatase (AKP), bacterial extracellular protein leakage and SDS-PAGE analysis were also used to investigate the antibacterial mechanism of chelerythrine. RESULTS: Analytic results of High Performance Liquid Chromatography showed that the content of chelerythrine (1.97 mg/g) in the ethyl acetate fraction was the highest, followed by those of methanol fraction and petroleum ether fraction. The in vitro anti-bacterial mechanisms of chelerythrine from T. asiatica were assessed. Chelerythrine showed strong antibacterial activities against Gram-positive bacteria, Staphylococcus aureus (SA), Methicillin-resistant S. aureus (MRSA), and extended spectrum ß-lactamase S. aureus (ESBLs-SA). The minimum inhibitory concentrations (MICs) of chelerythrine on three bacteria were all 0.156 mg/mL. Furthermore, results suggested that the primary anti-bacterial mechanism of chelerythrine may be attributed to its destruction of the channels across the bacterial cell membranes, causing protein leakage to the outside of the cell, and to its inhibition on protein biosynthesis. Images of scanning electron microscope revealed severe morphological changes in chelerythrine-treated bacteria except control, damage of parts of the cell wall and cell membrane as well as the leakage of some substances. CONCLUSIONS: Chelerythrine isolated from root of Toddalia asiatica (Linn) Lam possesses antibacterial activities through destruction of bacterial cell wall and cell membrance and inhibition of protein biosynthesis.


Assuntos
Antibacterianos/farmacologia , Benzofenantridinas/farmacologia , Raízes de Plantas/química , Rutaceae/química , Staphylococcus aureus , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Parede Celular/efeitos dos fármacos , Espaço Extracelular/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/citologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Microscopia Eletrônica , Extratos Vegetais/química , Staphylococcus aureus/citologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/ultraestrutura
16.
J Pharmacol Sci ; 137(4): 317-323, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30150143

RESUMO

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that is cross-resistant to most ß-lactam antibiotics. We investigated whether oxacillin, which is a ß-lactam antibiotic, alone or in combination with punicalagin can affect the penicillin binding protein 2a (PBP2a)-mediated resistance of MRSA. Susceptibility testing of punicalagin with oxacillin was performed using the microdilution and checkerboard assay and the growth curve assay. Binding affinity of punicalagin for cell wall peptidoglycan (PGN) was confirmed by an increased concentration of PGN in bacterial cultures containing punicalagin. The level of PBP2a was analyzed by western blotting. Punicalagin exhibited antimicrobial activity in the viability assay and increased the susceptibility of MRSA to oxacillin. PGN interfered with the antimicrobial activity of punicalagin and prevented the synergistic activity of punicalagin and oxacillin. Increasing the concentration of punicalagin and maintaining a constant concentration of oxacillin resulted in synergistic suppression of the expression of the mec operon (mecA, mecI, and mecR1). The production of PBP2a was suppressed by the addition of punicalagin to oxacillin. Our findings demonstrate that punicalagin potentiates the effect of oxacillin on MRSA by reducing the transcription of mecA (a gene marker for methicillin resistance), which resulted in a reduced level of PBP2a.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Taninos Hidrolisáveis/farmacologia , Resistência a Meticilina/efeitos dos fármacos , Resistência a Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxacilina/farmacologia , Proteínas de Ligação às Penicilinas/genética , Parede Celular/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Expressão Gênica/efeitos dos fármacos , Taninos Hidrolisáveis/metabolismo , Staphylococcus aureus Resistente à Meticilina/citologia , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana/métodos , Peptidoglicano/metabolismo , Transcrição Genética/efeitos dos fármacos
17.
Microb Pathog ; 124: 11-20, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30118800

RESUMO

Fast emerging antibiotic resistance in pathogens requires special attention for strengthening the reservoir of antimicrobial compounds. In view of this, several peptides with known antimicrobial activities have been reported to enhance the efficacy of antibiotics against multidrug resistant (MDR) pathogens. In the present study, potential of peptides having distinct mechanism of action, if any, was evaluated to improve the efficacy of conventional antibiotics against methicillin-resistant S. aureus (MRSA). After primary screening of six peptides, two peptides namely T3 and T4 showing very high minimum inhibitory concentrations (MICs) were selected to assess their role in altering the MICs of antibiotics to which the pathogen was resistant. In the presence of the peptides, the MICs of the antibiotics were found to be reduced as per the fractional inhibitory concentration indices (FICI) and time kill assay. These observations prompted us to look for their mechanism of action. The effect of peptides on the morphology of pathogen by field emission scanning electron microscopy (FE-SEM) revealed no damage to the cells at the sub-inhibitory concentrations of the peptide which correlated well with the higher MIC of the peptide, indicating no direct impact on the pathogen. However, dielectric spectroscopy, confocal microscopy and flow cytometry confirmed the interaction and localization of peptides with the bacterial membrane. The peptides were also found to inhibit efflux of ethidium bromide which is the substrate for many proteins involved in efflux system. Therefore, it is speculated that the peptides after interacting with the membrane of the pathogen might have resulted in the inhibition of the efflux of antibiotics thereby reducing their effective concentrations. The study thus suggests that peptides with no antimicrobial activity of their own, can also enhance the efficacy of the antibiotics by interacting with the pathogen thereby, acting as adjuvants for the antibiotics.


Assuntos
Ampicilina/farmacologia , Antibacterianos/farmacologia , Sinergismo Farmacológico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Oxacilina/farmacologia , Peptídeos/farmacologia , Membrana Celular/química , Espectroscopia Dielétrica , Citometria de Fluxo , Staphylococcus aureus Resistente à Meticilina/química , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Microscopia Confocal , Microscopia Eletrônica de Varredura , Ligação Proteica
18.
Small ; 14(35): e1801893, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30048039

RESUMO

Efficient capture and rapid detection of pathogenic bacteria from body fluids lead to early diagnostics of bacterial infections and significantly enhance the survival rate. We propose a universal nano/microfluidic device integrated with a 3D nanostructured detection platform for sensitive and quantifiable detection of pathogenic bacteria. Surface characterization of the nanostructured detection platform confirms a uniform distribution of hierarchical 3D nano-/microisland (NMI) structures with spatial orientation and nanorough protrusions. The hierarchical 3D NMI is the unique characteristic of the integrated device, which enables enhanced capture and quantifiable detection of bacteria via both a probe-free and immunoaffinity detection method. As a proof of principle, we demonstrate probe-free capture of pathogenic Escherichia coli (E. coli) and immunocapture of methicillin-resistant-Staphylococcus aureus (MRSA). Our device demonstrates a linear range between 50 and 104 CFU mL-1 , with average efficiency of 93% and 85% for probe-free detection of E. coli and immunoaffinity detection of MRSA, respectively. It is successfully demonstrated that the spatial orientation of 3D NMIs contributes in quantifiable detection of fluorescently labeled bacteria, while the nanorough protrusions contribute in probe-free capture of bacteria. The ease of fabrication, integration, and implementation can inspire future point-of-care devices based on nanomaterial interfaces for sensitive and high-throughput optical detection.


Assuntos
Escherichia coli/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Microfluídica/instrumentação , Microfluídica/métodos , Nanoestruturas/química , Simulação por Computador , Escherichia coli/ultraestrutura , Ouro/química , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Viabilidade Microbiana , Nanoestruturas/ultraestrutura , Propriedades de Superfície
19.
Sci Rep ; 8(1): 2411, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402952

RESUMO

Modern medicine is challenged continuously by the increasing prevalence of antibiotic resistant bacteria. Cationic antimicrobial peptides and their derivatives are interesting potential alternatives to antibiotics due to their rapid action, broad-spectrum of antimicrobial activity and limited emergence of bacterial resistance. This study reports the novel antimicrobial properties of histone H5, purified from chicken erythrocytes, and histone H5-derived synthetic peptides. Broth microdilution assays revealed that histone H5 has potent broad-spectrum antimicrobial activity against Gram-positive and Gram-negative planktonic bacteria (MIC range: 1.9 ± 1.8 to 4.9 ± 1.5 µg/mL), including vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Moreover, histone H5 displayed anti-biofilm activity against established Listeria monocytogenes and Pseudomonas aeruginosa biofilms. Scanning electron microscopy demonstrated bacterial membrane damage after histone H5 treatment, while a hemolytic assay revealed that histone H5 is non-toxic towards mammalian erythrocytes, even at a concentration of 1 mg/mL. Although the predicted H5-derived antimicrobial peptides tested in this study were located within the antimicrobial domain of histone H5, their synthetic versions did not possess more potent antimicrobial activity than the full length protein. Overall, this study demonstrates that histone H5 is a potent antimicrobial and therefore a promising template for the development of novel histone H5-derived antimicrobial peptides.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes/efeitos dos fármacos , Histonas/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Peptídeos/farmacologia , Enterococos Resistentes à Vancomicina/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Antibacterianos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Biofilmes/crescimento & desenvolvimento , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Galinhas , Relação Dose-Resposta a Droga , Eritrócitos/química , Hemólise/efeitos dos fármacos , Histonas/química , Histonas/isolamento & purificação , Listeria monocytogenes/efeitos dos fármacos , Listeria monocytogenes/crescimento & desenvolvimento , Listeria monocytogenes/ultraestrutura , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Testes de Sensibilidade Microbiana , Peptídeos/síntese química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/ultraestrutura , Alinhamento de Sequência , Relação Estrutura-Atividade , Enterococos Resistentes à Vancomicina/crescimento & desenvolvimento , Enterococos Resistentes à Vancomicina/ultraestrutura
20.
Sci Rep ; 8(1): 1021, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29348589

RESUMO

Escalating multidrug resistance and highly evolved virulence mechanisms have aggravated the clinical menace of methicillin-resistant Staphylococcus aureus (MRSA) infections. Towards development of economically viable staphylocidal agents here we report eight structurally novel tryptophan-arginine template based peptidomimetics. Out of the designed molecules, three lipopeptidomimetics (S-6, S-7 and S-8) containing 12-amino dodecanoic acid exhibited cell selectivity and good to potent activity against clinically relevant pathogens MRSA, methicillin-resistant Staphylococcus epidermidis and vancomycin-resistant Enterococcus faecium (MIC: 1.4-22.7 µg/mL). Mechanistically, the active peptidomimetics dissipated membrane potential and caused massive permeabilization on MRSA concomitant with loss of viability. Against stationary phase MRSA under nutrient-depleted conditions, active peptidomimetics S-7 and S-8 achieved > 6 log reduction in viability upon 24 h incubation while both S-7 (at 226 µg/mL) and S-8 (at 28 µg/mL) also destroyed 48 h mature MRSA biofilm causing significant decrease in viability (p < 0.05). Encouragingly, most active peptidomimetic S-8 maintained efficacy against MRSA in presence of serum/plasma while exhibiting no increase in MIC over 17 serial passages at sub-MIC concentrations implying resistance development to be less likely. Therefore, we envisage that the current template warrants further optimization towards the development of cell selective peptidomimetics for the treatment of device associated MRSA infections.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes/efeitos dos fármacos , Lipopeptídeos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Plâncton/efeitos dos fármacos , Animais , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Biomimética , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Desenho de Fármacos , Lipopeptídeos/síntese química , Lipopeptídeos/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/ultraestrutura , Camundongos , Testes de Sensibilidade Microbiana , Fatores de Tempo
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