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1.
Nat Commun ; 11(1): 4935, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33004797

RESUMO

Gramicidin A (1) is a peptide antibiotic that disrupts the transmembrane ion concentration gradient by forming an ion channel in a lipid bilayer. Although long used clinically, it is limited to topical application because of its strong hemolytic activity and mammalian cytotoxicity, likely arising from the common ion transport mechanism. Here we report an integrated high-throughput strategy for discovering analogues of 1 with altered biological activity profiles. The 4096 analogue structures are designed to maintain the charge-neutral, hydrophobic, and channel forming properties of 1. Synthesis of the analogues, tandem mass spectrometry sequencing, and 3 microscale screenings enable us to identify 10 representative analogues. Re-synthesis and detailed functional evaluations find that all 10 analogues share a similar ion channel function, but have different cytotoxic, hemolytic, and antibacterial activities. Our large-scale structure-activity relationship studies reveal the feasibility of developing analogues of 1 that selectively induce toxicity toward target organisms.


Assuntos
Antibacterianos/farmacologia , Descoberta de Drogas/métodos , Gramicidina/análogos & derivados , Ensaios de Triagem em Larga Escala/métodos , Animais , Antibacterianos/química , Linhagem Celular Tumoral , Química Farmacêutica , Eritrócitos , Estudos de Viabilidade , Bactérias Gram-Positivas/efeitos dos fármacos , Gramicidina/química , Gramicidina/farmacologia , Hemólise/efeitos dos fármacos , Concentração Inibidora 50 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Coelhos , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
2.
Nat Commun ; 11(1): 4608, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929085

RESUMO

Actinobacteria produce antibacterial and antifungal specialized metabolites. Many insects harbour actinobacteria on their bodies or in their nests and use these metabolites for protection. However, some actinobacteria produce metabolites that are toxic to insects and the evolutionary relevance of this toxicity is unknown. Here we explore chemical interactions between streptomycetes and the fruit fly Drosophila melanogaster. We find that many streptomycetes produce specialized metabolites that have potent larvicidal effects against the fly; larvae that ingest spores of these species die. The mechanism of toxicity is specific to the bacterium's chemical arsenal: cosmomycin D producing bacteria induce a cell death-like response in the larval digestive tract; avermectin producing bacteria induce paralysis. Furthermore, low concentrations of volatile terpenes like 2-methylisoborneol that are produced by streptomycetes attract fruit flies such that they preferentially deposit their eggs on contaminated food sources. The resulting larvae are killed during growth and development. The phenomenon of volatile-mediated attraction and specialized metabolite toxicity suggests that some streptomycetes pose an evolutionary risk to insects in nature.


Assuntos
Bactérias/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/microbiologia , Actinobacteria/fisiologia , Animais , Antraciclinas/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , Canfanos/toxicidade , Morte Celular/efeitos dos fármacos , Drosophila melanogaster/efeitos dos fármacos , Larva/efeitos dos fármacos , Larva/microbiologia , Metaboloma , Esporos Bacterianos/metabolismo , Esporos Bacterianos/fisiologia , Streptomyces/fisiologia , Análise de Sobrevida , Compostos Orgânicos Voláteis/farmacologia
3.
Sheng Wu Gong Cheng Xue Bao ; 36(8): 1650-1658, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32924363

RESUMO

Endophytic fungus is an important treasure trove for discovery of structurally unusual and biologically diverse compounds. A phytochemical investigation on a fungus Clonostachys rosea inhabits inner tissue of Blumea balsamifera (L.) DC. was initiatedrecently in our lab. Six pure compounds were isolated through silica gel column chromatography, sephadex LH-20, and semi-preparative HPLC techniques, with bio-guided strategy. Their structures were characterized as verticillin A (1), (S)-(+)-fusarinolic acid (2), 8-hydroxyfusaric acid (3), cerebroside C (4), 3-Maleimide-5-oxime (5), and bionectriol A (6) by analyses of NMR and MS data. All compounds were tested in vitro antibacterial activities against four strains of bacteria, Escherichia coli, Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa, and results revealed that 1, 4 and 6 display notableinhibition againstthree bacteria, with MIC values ranging from 2 to 16 µg/mL. Our findings provide references for mining novel antibiotics from endophytes originated from Li Minority medicinal plant B. balsamifera (L.) DC.


Assuntos
Antibacterianos , Asteraceae , Hypocreales , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Asteraceae/microbiologia , Bactérias/efeitos dos fármacos , Endófitos , Hypocreales/química , Hypocreales/metabolismo , Testes de Sensibilidade Microbiana
4.
Adv Exp Med Biol ; 1267: 117-133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894480

RESUMO

Antibiotic resistance is a global epidemic, becoming increasingly pressing due to its rapid spread. There is thus a critical need to develop new therapeutic approaches. In addition to searching for new antibiotics, looking into existing mechanisms of natural host defense may enable researchers to improve existing defense mechanisms, and to develop effective, synthetic drugs guided by natural principles. Histones, primarily known for their role in condensing mammalian DNA, are antimicrobial and share biochemical similarities with antimicrobial peptides (AMPs); however, the mechanism by which histones kill bacteria is largely unknown. Both AMPs and histones are similar in size, cationic, contain a high proportion of hydrophobic amino acids, and possess the ability to form alpha helices. AMPs, which mostly kill bacteria through permeabilization or disruption of the biological membrane, have recently garnered significant attention for playing a key role in host defenses. This chapter outlines the structure and function of histone proteins as they compare to AMPs and provides an overview of their role in innate immune responses, especially regarding the action of specific histones against microorganisms and their potential mechanism of action against microbial pathogens.


Assuntos
Antibacterianos/química , Antibacterianos/imunologia , Bactérias/imunologia , Histonas/química , Histonas/imunologia , Animais , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Histonas/farmacologia , Imunidade Inata
5.
Mar Drugs ; 18(10)2020 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-32993146

RESUMO

For a long time, algal chemistry from terrestrial to marine or freshwater bodies, especially chlorophytes, has fascinated numerous investigators to develop new drugs in the nutraceutical and pharmaceutical industries. As such, chlorophytes comprise a diverse structural class of secondary metabolites, having functional groups that are specific to a particular source. All bioactive compounds of chlorophyte are of great interest due to their supplemental/nutritional/pharmacological activities. In this review, a detailed description of the chemical diversity of compounds encompassing alkaloids, terpenes, steroids, fatty acids and glycerides, their subclasses and their structures are discussed. These promising natural products have efficiency in developing new drugs necessary in the treatment of various deadly pathologies (cancer, HIV, SARS-CoV-2, several inflammations, etc.). Marine chlorophyte, therefore, is portrayed as a pivotal treasure in the case of drugs having marine provenience. It is a domain of research expected to probe novel pharmaceutically or nutraceutically important secondary metabolites resulting from marine Chlorophyta. In this regard, our review aims to compile the isolated secondary metabolites having diverse chemical structures from chlorophytes (like Caulerpa ssp., Ulva ssp., Tydemania ssp., Penicillus ssp., Codium ssp., Capsosiphon ssp., Avrainvillea ssp.), their biological properties, applications and possible mode of action.


Assuntos
Produtos Biológicos/farmacologia , Clorófitas/química , Clorófitas/metabolismo , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Produtos Biológicos/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Humanos , Neoplasias/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia
6.
Nat Commun ; 11(1): 4465, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901012

RESUMO

Titanium implants have been widely used in bone tissue engineering for decades. However, orthopedic implant-associated infections increase the risk of implant failure and even lead to amputation in severe cases. Although TiO2 has photocatalytic activity to produce reactive oxygen species (ROS), the recombination of generated electrons and holes limits its antibacterial ability. Here, we describe a graphdiyne (GDY) composite TiO2 nanofiber that combats implant infections through enhanced photocatalysis and prolonged antibacterial ability. In addition, GDY-modified TiO2 nanofibers exert superior biocompatibility and osteoinductive abilities for cell adhesion and differentiation, thus contributing to the bone tissue regeneration process in drug-resistant bacteria-induced implant infection.


Assuntos
Antibacterianos/química , Grafite , Nanofibras/química , Próteses e Implantes , Infecções Relacionadas à Prótese/prevenção & controle , Titânio , Células 3T3 , Animais , Materiais Biocompatíveis/química , Regeneração Óssea , Sobrevivência Celular , Modelos Animais de Doenças , Feminino , Teste de Materiais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Nanocompostos/química , Osteogênese , Processos Fotoquímicos , Infecções Estafilocócicas/prevenção & controle
7.
Proc Natl Acad Sci U S A ; 117(37): 22967-22973, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32868444

RESUMO

Hospital-acquired infections are a global health problem that threatens patients' treatment in intensive care units, causing thousands of deaths and a considerable increase in hospitalization costs. The endotracheal tube (ETT) is a medical device placed in the patient's trachea to assist breathing and delivering oxygen into the lungs. However, bacterial biofilms forming at the surface of the ETT and the development of multidrug-resistant bacteria are considered the primary causes of ventilator-associated pneumonia (VAP), a severe hospital-acquired infection for significant mortality. Under these circumstances, there has been a need to administrate antibiotics together. Although necessary, it has led to a rapid increase in bacterial resistance to antibiotics. Therefore, it becomes necessary to develop alternatives to prevent and combat these bacterial infections. One possibility is to turn the ETT itself into a bactericide. Some examples reported in the literature present drawbacks. To overcome those issues, we have designed a photosensitizer-containing ETT to be used in photodynamic inactivation (PDI) to avoid bacteria biofilm formation and prevent VAP occurrence during tracheal intubation. This work describes ETT's functionalization with curcumin photosensitizer, as well as its evaluation in PDI against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli A significant photoinactivation (up to 95%) against Gram-negative and Gram-positive bacteria was observed when curcumin-functionalized endotracheal (ETT-curc) was used. These remarkable results demonstrate this strategy's potential to combat hospital-acquired infections and contribute to fighting antimicrobial resistance.


Assuntos
Antibacterianos/farmacologia , Curcumina/farmacologia , Intubação Intratraqueal/instrumentação , Pneumonia Associada à Ventilação Mecânica/prevenção & controle , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Curcumina/química , Humanos , Intubação Intratraqueal/efeitos adversos , Pneumonia Associada à Ventilação Mecânica/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
8.
PLoS One ; 15(9): e0237948, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32877437

RESUMO

The lack of new antibiotics necessitates the improvement of existing ones, many of which are limited by toxic side effects. Aminoglycosides, antibiotics with excellent activity and low bacterial resistance, are hampered by dose-dependent toxic effects in patients (nephrotoxicity, ototoxicity). High antibiotic concentrations are often required to treat dormant, non-dividing bacteria, though previous studies show that aminoglycosides can be activated against such bacteria by specific metabolites. Here, we employed this mechanism to greatly boost the activity of low concentrations of aminoglycosides against prevalent Gram-negative pathogens (Escherichia coli, Salmonella enterica, and Klebsiella pneumoniae), suggesting that less toxic drug concentrations might be used effectively in patients. We go on to show that this effect improved treatment of biofilms, did not increase aminoglycoside resistance, and was due to the generation of proton-motive force (PMF). By single-cell microscopy, we demonstrate that stationary-phase cells, while non-dividing, actively maintain a growth-arrested state that is not reversed by metabolite addition. Surprisingly, within starved populations, we observed rare cells (3%) that divided without added nutrients. Additionally, we discovered that mannitol could directly protect human kidney cells from aminoglycoside cytotoxicity, independent of the metabolite's effect on bacteria. This work forwards a mechanism-based strategy to improve existing antibiotics by mitigating their toxic side effects.


Assuntos
Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Antibacterianos/farmacologia , Bactérias/crescimento & desenvolvimento , Infecções Bacterianas/tratamento farmacológico , Biofilmes/crescimento & desenvolvimento , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Antibacterianos/química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/microbiologia , Infecções Bacterianas/patologia , Biofilmes/efeitos dos fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana
9.
PLoS Comput Biol ; 16(8): e1007898, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797038

RESUMO

New treatments for diseases caused by antimicrobial-resistant microorganisms can be developed by identifying unexplored therapeutic targets and by designing efficient drug screening protocols. In this study, we have screened a library of compounds to find ligands for the flavin-adenine dinucleotide synthase (FADS) -a potential target for drug design against tuberculosis and pneumonia- by implementing a new and efficient virtual screening protocol. The protocol has been developed for the in silico search of ligands of unexplored therapeutic targets, for which limited information about ligands or ligand-receptor structures is available. It implements an integrative funnel-like strategy with filtering layers that increase in computational accuracy. The protocol starts with a pharmacophore-based virtual screening strategy that uses ligand-free receptor conformations from molecular dynamics (MD) simulations. Then, it performs a molecular docking stage using several docking programs and an exponential consensus ranking strategy. The last filter, samples the conformations of compounds bound to the target using MD simulations. The MD conformations are scored using several traditional scoring functions in combination with a newly-proposed score that takes into account the fluctuations of the molecule with a Morse-based potential. The protocol was optimized and validated using a compound library with known ligands of the Corynebacterium ammoniagenes FADS. Then, it was used to find new FADS ligands from a compound library of 14,000 molecules. A small set of 17 in silico filtered molecules were tested experimentally. We identified five inhibitors of the activity of the flavin adenylyl transferase module of the FADS, and some of them were able to inhibit growth of three bacterial species: C. ammoniagenes, Mycobacterium tuberculosis, and Streptococcus pneumoniae, where the last two are human pathogens. Overall, the results show that the integrative VS protocol is a cost-effective solution for the discovery of ligands of unexplored therapeutic targets.


Assuntos
Antibacterianos , Proteínas de Bactérias , Nucleotidiltransferases , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Corynebacterium/efeitos dos fármacos , Corynebacterium/enzimologia , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Ligantes , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Nucleotidiltransferases/antagonistas & inibidores , Nucleotidiltransferases/química , Nucleotidiltransferases/metabolismo
10.
PLoS Comput Biol ; 16(8): e1008106, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32797079

RESUMO

Antibiotic resistance is rising and we urgently need to gain a better quantitative understanding of how antibiotics act, which in turn would also speed up the development of new antibiotics. Here, we describe a computational model (COMBAT-COmputational Model of Bacterial Antibiotic Target-binding) that can quantitatively predict antibiotic dose-response relationships. Our goal is dual: We address a fundamental biological question and investigate how drug-target binding shapes antibiotic action. We also create a tool that can predict antibiotic efficacy a priori. COMBAT requires measurable biochemical parameters of drug-target interaction and can be directly fitted to time-kill curves. As a proof-of-concept, we first investigate the utility of COMBAT with antibiotics belonging to the widely used quinolone class. COMBAT can predict antibiotic efficacy in clinical isolates for quinolones from drug affinity (R2>0.9). To further challenge our approach, we also do the reverse: estimate the magnitude of changes in drug-target binding based on antibiotic dose-response curves. We overexpress target molecules to infer changes in antibiotic-target binding from changes in antimicrobial efficacy of ciprofloxacin with 92-94% accuracy. To test the generality of our approach, we use the beta-lactam ampicillin to predict target molecule occupancy at MIC from antimicrobial action with 90% accuracy. Finally, we apply COMBAT to predict antibiotic concentrations that can select for resistance due to novel resistance mutations. Using ciprofloxacin and ampicillin as well defined test cases, our work demonstrates that drug-target binding is a major predictor of bacterial responses to antibiotics. This is surprising because antibiotic action involves many additional effects downstream of drug-target binding. In addition, COMBAT provides a framework to inform optimal antibiotic dose levels that maximize efficacy and minimize the rise of resistant mutants.


Assuntos
Antibacterianos , Biologia Computacional/métodos , Desenvolvimento de Medicamentos/métodos , Quinolonas , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Relação Dose-Resposta a Droga , Farmacorresistência Bacteriana/efeitos dos fármacos , Enterobacteriaceae/efeitos dos fármacos , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Modelos Biológicos , Quinolonas/administração & dosagem , Quinolonas/química , Quinolonas/metabolismo , Quinolonas/farmacologia
11.
Sci Rep ; 10(1): 13875, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32807805

RESUMO

Respiratory protection is key in infection prevention of airborne diseases, as highlighted by the COVID-19 pandemic for instance. Conventional technologies have several drawbacks (i.e., cross-infection risk, filtration efficiency improvements limited by difficulty in breathing, and no safe reusability), which have yet to be addressed in a single device. Here, we report the development of a filter overcoming the major technical challenges of respiratory protective devices. Large-pore membranes, offering high breathability but low bacteria capture, were functionalized to have a uniform salt layer on the fibers. The salt-functionalized membranes achieved high filtration efficiency as opposed to the bare membrane, with differences of up to 48%, while maintaining high breathability (> 60% increase compared to commercial surgical masks even for the thickest salt filters tested). The salt-functionalized filters quickly killed Gram-positive and Gram-negative bacteria aerosols in vitro, with CFU reductions observed as early as within 5 min, and in vivo by causing structural damage due to salt recrystallization. The salt coatings retained the pathogen inactivation capability at harsh environmental conditions (37 °C and a relative humidity of 70%, 80% and 90%). Combination of these properties in one filter will lead to the production of an effective device, comprehensibly mitigating infection transmission globally.


Assuntos
Filtros de Ar/microbiologia , Antibacterianos/química , Betacoronavirus , Infecções por Coronavirus/prevenção & controle , Máscaras/microbiologia , Membranas Artificiais , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Dispositivos de Proteção Respiratória/microbiologia , Cloreto de Sódio/química , Aerossóis , Antibacterianos/farmacologia , Infecções por Coronavirus/transmissão , Infecções por Coronavirus/virologia , Cristalização , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Temperatura Alta , Humanos , Umidade , Pneumonia Viral/transmissão , Pneumonia Viral/virologia , Cloreto de Sódio/farmacologia
12.
J Chromatogr A ; 1626: 461371, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797850

RESUMO

Effect of mobile phase (water-methanol) composition on the enantioseparation of dipeptides on the chiral stationary phase Chirobiotic R was investigated using Ala-Ala, Leu-Leu, Gly-Leu, and Leu-Gly as case studies. The lipophilicity of dipeptides was found to be an essential factor in the dependence of their retention on the methanol percentage, the retention factor of lipophobic dipeptides increasing monotonously and that of lipophilic dipeptides changing according to an asymmetric U-shaped trajectory as methanol concentration increases. The behavior of enantioselectivity as a function of the methanol content also depends on the lipophilicity of dipeptide. For lipophilic Leu-Leu, the dependence has a dome-like shape, and for more lipophobic dipeptides, Ala-Ala and Gly-Leu, it is an increasing function of the methanol concentration. The importance of solvation equilibria in the bulk liquid and on the surface of the stationary phase for the total retention is discussed from the thermodynamic point of view. Special consideration is given to the adsorption of the water-methanol mixture on the surface of the Chirobiotic R stationary phase.


Assuntos
Antibacterianos/química , Cromatografia Líquida de Alta Pressão/métodos , Dipeptídeos/química , Metanol/química , Adsorção , Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Termodinâmica
13.
PLoS One ; 15(8): e0237258, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756605

RESUMO

Aquatic weeds such as muskgrass (Chara spp.), water hyacinth (Eichhornia crassipes), water lettuce (Pistia stratiotes), hydrilla (Hydrilla verticillate), filamentous algae (Lyngbya wollei), and duckweed (Lemna minor) thrive in farm canals within the Everglades Agricultural Area of South Florida. Their presence, particularly during the summer months is an environmental concern with regards to water quality, in addition to being a nuisance because of their ability to multiply and spread rapidly in open waters causing restricted drainage/irrigation flow and low dissolved oxygen levels. Chemical control is effective but can have undesirable off-target effects, so reduced herbicide use is desirable. Hence, need exists to discover ways in which these weeds could be best managed or utilized. The objective of this research was to evaluate the allelopathic effect of these weeds to determine their use as potential biopesticides. Six aqueous extracts were tested against 100 bacterial strains isolated from plants and soil to evaluate their antimicrobial activity. These extracts were also used to determine their insecticidal and antifeedant effects on fall armyworm (FAW, Spodoptera frugiperda). Both extracts and powder form of the aquatic weeds were tested for their herbicidal activity towards seed germination and growth of three common terrestrial weed species. At a dilution of 1:100 and 1:1,000, none of the aquatic weeds inhibited in-vitro growth of the bacterial strains, with one exception (filamentous algae extract at 1:100 reduced growth of one bacterial isolate by 54%). Water lettuce reduced the survival rate of FAW by 14% while hydrilla and duckweed caused 11% and 9% reduction of FAW growth, respectively. Powdered duckweed inhibited the growth of nutsedge by 41%, whereas filamentous algae powder and extract reduced germination of amaranth by 20% and 28%, respectively. Harvesting these weeds and converting them into useable compounds could not only eliminate the in situ farm canal and water quality problems but also result in development of new soil amendments or biopesticides.


Assuntos
Antibacterianos/toxicidade , Agentes de Controle Biológico/toxicidade , Plantas Daninhas/química , Agricultura , Animais , Antibacterianos/química , Bactérias/efeitos dos fármacos , Agentes de Controle Biológico/química , Cianobactérias/química , Eichhornia/química , Hydrocharitaceae/química , Inseticidas/química , Inseticidas/toxicidade , Plantas/microbiologia , Microbiologia do Solo , Spodoptera/efeitos dos fármacos
14.
Int J Nanomedicine ; 15: 5147-5163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764942

RESUMO

Background: In the last decades, nosocomial infections caused by drug-resistant Pseudomonas aeruginosa became a common problem in healthcare facilities. Antibiotics are becoming less effective as new resistant strains appear. Therefore, the development of novel enhanced activity antibacterial agents becomes very significant. A combination of nanomaterials with different physical and chemical properties enables us to generate novel multi-functional derivatives. In this study, graphene oxide and polyvinylpyrrolidone-stabilized silver nanoparticles hybrid nanocomposite (GO-Ag HN) were synthesized. The relation between antibiotic resistance and GO-Ag HN potential toxicity to clinical P. aeruginosa strains, their antibiotic resistance, and molecular mechanisms were assessed. Methods: Chemical state, particle size distribution, and morphology of synthesized GO-Ag NH were investigated using spectroscopy and microscopy techniques (UV-Vis, FTIR, XPS, TEM, SEM, AFM). Broad-spectrum antibiotic resistance of P. aeruginosa strains was determined using E-test. Antibiotic resistance genes were identified using polymerase chain reaction (PCR). Results: In this study, the toxicity of the GO-Ag NH to the isolated clinical P. aeruginosa strains has been investigated. A high antibiotic resistance level (92%) was found among P. aeruginosa strains. The most prevalent antibiotic resistance gene among tested strains was the AMPC beta-lactamase gene (65.6%). UV-vis, FTIR, and XPS studies confirmed the formation of the silver nanoparticles on the GO nanosheets. The functionalization process occurred through the interaction between Ag nanoparticles, GO, and polyvinylpyrrolidone used for nanoparticle stabilization. SEM analysis revealed that GO nanosheets undergo partial fragmentation during hybrid nanocomposite preparation, which remarkably increases the number of sharp edges and their mediated cutting effect. TEM analysis showed that GO-Ag HN spherical Ag nanoparticles mainly 9-12 nm in size were irregularly precipitated on the GO nanosheet surface. A higher density of Ag NPs was observed in the sheets' wrinkles, corrugations, and sharp edges. This hybrid nanocomposite poses enhanced antibacterial activity against carbapenem-resistant P. aeruginosa strains through a possible synergy between toxicity mechanisms of GO nanosheets and Ag nanoparticles. With incubation time increasing up to 10 minutes, the survival of P. aeruginosa decreased significantly. Conclusion: A graphene oxide and silver nanoparticles hybrid composite has been shown to be a promising material to control nosocomial infections caused by bacteria strains resistant to most antibiotics.


Assuntos
Farmacorresistência Bacteriana/genética , Grafite/química , Grafite/farmacologia , Nanopartículas Metálicas/química , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Prata/química , Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos
15.
Proc Natl Acad Sci U S A ; 117(34): 20530-20537, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32817463

RESUMO

Sarecycline is a new narrow-spectrum tetracycline-class antibiotic approved for the treatment of acne vulgaris. Tetracyclines share a common four-ring naphthacene core and inhibit protein synthesis by interacting with the 70S bacterial ribosome. Sarecycline is distinguished chemically from other tetracyclines because it has a 7-[[methoxy(methyl)amino]methyl] group attached at the C7 position of ring D. To investigate the functional role of this C7 moiety, we determined the X-ray crystal structure of sarecycline bound to the Thermus thermophilus 70S ribosome. Our 2.8-Å resolution structure revealed that sarecycline binds at the canonical tetracycline binding site located in the decoding center of the small ribosomal subunit. Importantly, unlike other tetracyclines, the unique C7 extension of sarecycline extends into the messenger RNA (mRNA) channel to form a direct interaction with the A-site codon to possibly interfere with mRNA movement through the channel and/or disrupt A-site codon-anticodon interaction. Based on our biochemical studies, sarecycline appears to be a more potent initiation inhibitor compared to other tetracyclines, possibly due to drug interactions with the mRNA, thereby blocking accommodation of the first aminoacyl transfer RNA (tRNA) into the A site. Overall, our structural and biochemical findings rationalize the role of the unique C7 moiety of sarecycline in antibiotic action.


Assuntos
Antibacterianos/farmacologia , Ribossomos/efeitos dos fármacos , Tetraciclinas/farmacologia , Antibacterianos/química , RNA Ribossômico 16S/química , Tetraciclinas/química , Thermus thermophilus
16.
Int J Nanomedicine ; 15: 4991-5004, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764931

RESUMO

Introduction: Various materials and approaches have been used to reduce the mesh-induced inflammatory response and modify the mesh with tissue-matched mechanical properties, aiming to improve the repair of abdominal wall defects. Materials and Methods: In this study, we fabricated a polycaprolactone (PCL)/silk fibroin (SF) mesh integrated with amoxicillin (AMX)-incorporating multiwalled carbon nanotubes (MWCNTs) via electrospinning, grafting and crosslinking, developing a sustainable antibiotic and flexible mesh. AMX was loaded into the hollow tubular MWCNTs by physical adsorption, and a nanofibrous structure was constructed by electrospinning PCL and SF (40:60 w/w). The AMX@MWCNTs were then chemically grafted onto the surfaces of the PCL/SF nanofibers by treating with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) solution for simultaneous crosslinking and coating. The incorporation of AMX into the MWCNTs (AMX@MWCNTs) and the integration of the AMX@MWCNTs with the PCL/SF nanofibers were characterized. Then, the functional mesh was fabricated and fully evaluated in terms of antibacterial activity, mechanical properties and host response. Results: Our results demonstrated that the PCL/SF nanofibrous structure was fabricated successfully by electrospinning. After integrating with AMX@MWCNT by grafting and crosslinking, the functional mesh showed undeformed structure, modified surface hydrophilicity and biocompatible interfaces, abdominal wall-matched mechanical properties, and a sustained-release antibiotic profile in E. coli growth inhibition compared to those of PCL/SF mesh in vitro. In a rat model with subcutaneous implantation, the functional mesh incited less mesh-induced inflammatory and foreign body responses than PCL/SF mesh within 14 days. The histological analysis revealed less infiltration of granulocytes and macrophages during this period, resulting in the loosely packed collagen deposition on the functional mesh and prominent collagen incorporation. Discussion: Therefore, this designed PCL/SF-AMX@MWCNT nanofibrous mesh, functionalized with antibacterial and tissue-matched mechanical properties, provides a promising alternative for the repair of abdominal wall defects.


Assuntos
Amoxicilina/química , Antibacterianos/química , Nanofibras/química , Nanotecnologia/métodos , Telas Cirúrgicas , Amoxicilina/farmacocinética , Amoxicilina/farmacologia , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Colágeno/química , Colágeno/metabolismo , Reagentes para Ligações Cruzadas/química , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fibroínas/química , Inflamação/etiologia , Masculino , Teste de Materiais , Camundongos , Nanotubos de Carbono/química , Poliésteres/química , Ratos Sprague-Dawley , Telas Cirúrgicas/efeitos adversos
17.
Int J Nanomedicine ; 15: 5027-5042, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764934

RESUMO

Background: Bactericidal capacity, durable inhibition of biofilm formation, and a three-dimensional (3D) porous structure are the emphases of infected bone defect (IBD) treatment via local scaffold implantation strategy. Purpose: In this study, silver nanoparticle (AgNP)-loaded nano-hydroxyapatite (nHA)@ reduced graphene oxide (RGO) 3D scaffolds (AHRG scaffolds) were designed to alleviate bone infection, inhibit biofilm formation, and promote bone repair through the synergistic effects of AgNPs, RGO, and nHA. Materials and Methods: AHRGs were prepared using a one-step preparation method, to create a 3D porous scaffold to facilitate a uniform distribution of AgNPs and nHA. Methicillin-resistant Staphylococcus aureus (MRSA) was used as a model-resistant bacterium, and the effects of different silver loadings on the antimicrobial activity and cytocompatibility of materials were evaluated. Finally, a rabbit IBD model was used to evaluate the therapeutic effect of the AHRG scaffold in vivo. Results: The results showed successful synthesis of the AHRG scaffold. The ideal 3D porous structure was verified using scanning electron microscopy and transmission electron microscopy, and X-ray photoelectron spectroscopy and selected area electron diffraction measurements revealed uniform distributions of AgNP and nHA. In vitro antibacterial and cytocompatibility indicated that the 4% AHRG scaffolds possessed the most favorable balance of bactericidal properties and cytocompatibility. In vivo evaluation of the IBD model showed promising treatment efficacy of AHRG scaffolds. Conclusion: The as-fabricated AHRG scaffolds effectively eliminated infection and inhibited biofilm formation. IBD repair was facilitated by the bactericidal properties and 3D porous structure of the AHRG scaffold, suggesting its potential in the treatment of IBDs.


Assuntos
Antibacterianos/farmacologia , Doenças Ósseas Infecciosas/terapia , Grafite/química , Nanopartículas Metálicas/química , Engenharia Tecidual/métodos , Tecidos Suporte/química , Animais , Antibacterianos/química , Biofilmes/efeitos dos fármacos , Regeneração Óssea/efeitos dos fármacos , Substitutos Ósseos , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças , Durapatita/química , Feminino , Masculino , Teste de Materiais , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Porosidade , Coelhos , Ratos , Prata/química , Prata/farmacologia , Infecções Estafilocócicas/terapia
18.
Int J Nanomedicine ; 15: 5473-5489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801701

RESUMO

Introduction: Biofilms protect bacteria from antibiotics and this can produce drug-resistant strains, especially the main pathogen of periodontitis, Porphyromonas gingivalis. Carbon quantum dots with various biomedical properties are considered to have great application potential in antibacterial and anti-biofilm treatment. Methods: Tinidazole carbon quantum dots (TCDs) and metronidazole carbon quantum dots (MCDs) were prepared by a hydrothermal method with the clinical antibacterial drugs tinidazole and metronidazole, respectively. Then, TCDs and MCDs were characterized by transmission electron microscopy, UV-visible spectroscopy, infrared spectroscopy and energy-dispersive spectrometry. The antibacterial effects were also investigated under different conditions. Results: The TCDs and MCDs had uniform sizes. The results of UV-visible and energy-dispersive spectrometry confirmed their important carbon polymerization structures and the activity of the nitro group, which had an evident inhibitory effect on P. gingivalis, but almost no effect on other bacteria, including Escherichia coli, Staphylococcus aureus and Prevotella nigrescens. Importantly, the TCDs could penetrate the biofilms to further effectively inhibit the growth of P. gingivalis under the biofilms. Furthermore, it was found that the antibacterial effect of TCDs lies in its ability to impair toxicity by inhibiting the major virulence factors and related genes involved in the biofilm formation of P. gingivalis, thus affecting the self-assembly of biofilm-related proteins. Conclusion: The findings demonstrate a promising new method for improving the efficiency of periodontitis treatment by penetrating the P. gingivalis biofilm with preparations of nano-level antibacterial drugs.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Porphyromonas gingivalis/efeitos dos fármacos , Pontos Quânticos/química , Animais , Antibacterianos/efeitos adversos , Aderência Bacteriana/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Carbono/química , Carbono/farmacologia , Escherichia coli/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Metronidazol/química , Metronidazol/farmacologia , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Transmissão , Periodontite/microbiologia , Porphyromonas gingivalis/genética , Porphyromonas gingivalis/fisiologia , Coelhos , Espectrofotometria Ultravioleta , Staphylococcus aureus/efeitos dos fármacos , Tinidazol/química , Tinidazol/farmacologia , Fatores de Virulência/antagonistas & inibidores
19.
Nat Commun ; 11(1): 3894, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753597

RESUMO

Here, we demonstrate the self-assembly of the antimicrobial human LL-37 active core (residues 17-29) into a protein fibril of densely packed helices. The surface of the fibril encompasses alternating hydrophobic and positively charged zigzagged belts, which likely underlie interactions with and subsequent disruption of negatively charged lipid bilayers, such as bacterial membranes. LL-3717-29 correspondingly forms wide, ribbon-like, thermostable fibrils in solution, which co-localize with bacterial cells. Structure-guided mutagenesis analyses supports the role of self-assembly in antibacterial activity. LL-3717-29 resembles, in sequence and in the ability to form amphipathic helical fibrils, the bacterial cytotoxic PSMα3 peptide that assembles into cross-α amyloid fibrils. This argues helical, self-assembling, basic building blocks across kingdoms of life and points to potential structural mimicry mechanisms. The findings expose a protein fibril which performs a biological activity, and offer a scaffold for functional and durable biomaterials for a wide range of medical and technological applications.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias/efeitos dos fármacos , Amiloide/metabolismo , Animais , Peptídeos Catiônicos Antimicrobianos/genética , Bactérias/metabolismo , Benzotiazóis , Catelicidinas/farmacologia , Cristalografia por Raios X , Gorilla gorilla , Humanos , Testes de Sensibilidade Microbiana , Micrococcus luteus/efeitos dos fármacos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Modelos Moleculares , Conformação Proteica , Staphylococcus hominis/efeitos dos fármacos , Difração de Raios X
20.
Phys Rev Lett ; 125(3): 033604, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32745420

RESUMO

We demonstrate Bragg diffraction of the antibiotic ciprofloxacin and the dye molecule phthalocyanine at a thick optical grating. The observed patterns show a single dominant diffraction order with the expected dependence on the incidence angle as well as oscillating population transfer between the undiffracted and diffracted beams. We achieve an equal-amplitude splitting of 14ℏk (photon momenta) and maximum momentum transfer of 18ℏk. This paves the way for efficient, large-momentum beam splitters and mirrors for hot and complex molecules.


Assuntos
Ciprofloxacino/química , Indóis/química , Modelos Químicos , Antibacterianos/química , Interferometria/métodos , Modelos Moleculares , Pigmentos Biológicos/química , Espalhamento de Radiação
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