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1.
An Acad Bras Cienc ; 92(2): e20200466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32556054

RESUMO

COVID-19 emerged in December 2019 in China, and since then, has disrupted global public health and changed economic paradigms. In dealing with the new Coronavirus, SARS-CoV-2, the world has not faced such extreme global fragility since the "Spanish flu" pandemic in 1918. Researchers globally are dedicating efforts to the search for an effective treatment for COVID-19. Drugs already used in a clinical setting for other pathologies have been tested as a new therapeutic approach against SARS-CoV-2, setting off a frenzy over the preliminary data of different studies. This work aims to compile and discuss the data published thus far. Despite the potential effects of some antivirals and antiparasitic against COVID-19, clinical studies must confirm real effectiveness. However, non-pharmacological approaches have proven to be the most efficient strategy to date.


Assuntos
Antibacterianos/administração & dosagem , Antiparasitários/administração & dosagem , Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Macrolídeos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Inibidores de Serino Proteinase/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacologia , Antiparasitários/química , Antiparasitários/farmacologia , Antivirais/química , Antivirais/farmacologia , Humanos , Macrolídeos/química , Macrolídeos/farmacologia , Pandemias , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia
2.
Biosci Trends ; 14(2): 159-160, 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32249257

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic that has developed in late 2019 and 2020 is a serious threat to human health. With no vaccines or drugs approved for prevention and treatment until now, all efforts at drug design and/or clinical trials of already approved drugs are worthy and creditable. Using structure-based drug selection for identification of SARS-CoV-2 protease inhibitors, old drugs such as macrolides (MAC) were predicted to be effective for COVID-19. Lately, the anti-viral effects of macrolides have attracted considerable attention. Very recently, hydroxychloroquine in combination with azithromycin treatment was reported to be effective for COVID-19. We believe that treatments with macrolides alone or in combination with other drugs are promising and open the possibility of an international strategy to fight this emerging viral infection.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Macrolídeos/farmacologia , Pneumonia Viral/tratamento farmacológico , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/enzimologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Macrolídeos/química , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade
3.
BMC Infect Dis ; 20(1): 314, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32345231

RESUMO

BACKGROUND: Mycoplasma genitalium is an emerging sexually transmitted infection, with increasing rates of resistance to fluroquinolones and macrolides, the recommended treatments. Despite this, M. genitalium is not part of routine screening for Sexually Transmitted Infections (STIs) in many countries and the prevalence of infection and patterns of disease remain to be determined in many populations. Such data is of particular importance in light of the reported rise in antibiotic resistance in M. genitalium isolates. METHODS: Urine and urethral swab samples were collected from the primary public sexual health clinic in Singapore and tested for C. trachomatis (CT) or N. gonorrhoeae (NG) infection and for the presence of M. genitalium. Antibiotic resistance in M. genitalium strains detected was determined by screening for genomic mutations associated with macrolide and fluroquinolone resistance. RESULTS: We report the results of a study into M. genitalium prevalence at the national sexual health clinic in Singapore. M. genitalium was heavily associated with CT infection (8.1% of cases), but present in only of 2.4% in CT negative cases and not independently linked to NG infection. Furthermore, we found high rates of resistance mutations to both macrolides (25%) and fluoroquinolones (37.5%) with a majority of resistant strains being dual-resistant. Resistance mutations were only found in strains from patients with CT co-infection. CONCLUSIONS: Our results support targeted screening of CT positive patients for M. genitalium as a cost-effective strategy to reduce the incidence of M. genitalium in the absence of comprehensive routine screening. The high rate of dual resistance also highlights the need to ensure the availability of alternative antibiotics for the treatment of multi-drug resistant M. genitalium isolates.


Assuntos
Antibacterianos/farmacologia , Infecções por Chlamydia/diagnóstico , Chlamydia trachomatis/efeitos dos fármacos , Farmacorresistência Bacteriana Múltipla , Infecções por Mycoplasma/diagnóstico , Mycoplasma genitalium/efeitos dos fármacos , Instituições de Assistência Ambulatorial , Antibacterianos/uso terapêutico , Infecções por Chlamydia/complicações , Infecções por Chlamydia/tratamento farmacológico , Chlamydia trachomatis/genética , Chlamydia trachomatis/isolamento & purificação , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Fluoroquinolonas/farmacologia , Fluoroquinolonas/uso terapêutico , Humanos , Macrolídeos/farmacologia , Macrolídeos/uso terapêutico , Infecções por Mycoplasma/complicações , Infecções por Mycoplasma/tratamento farmacológico , Infecções por Mycoplasma/epidemiologia , Mycoplasma genitalium/genética , Mycoplasma genitalium/isolamento & purificação , Prevalência , RNA Ribossômico 23S/química , RNA Ribossômico 23S/genética , RNA Ribossômico 23S/metabolismo , Análise de Sequência de DNA , Singapura/epidemiologia , Uretra/microbiologia
4.
J Med Microbiol ; 69(4): 505-520, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32159507

RESUMO

Introduction. Streptococcus pneumoniae is responsible for many community infections, with the main ones being pneumonia and meningitis. Pneumococcus has developed increased resistance to multiple classes of antibiotics. The evolution of antibiotic resistance in pneumococcus was influenced by changes in serotype distribution under vaccine selection pressure.Aim. The aim of this study was to determine the genes involved in macrolide resistance, the antimicrobial susceptibility, the serotype distribution and the spread of international antibiotic-resistant clones among clinical isolates of S. pneumoniae.Methodology. We investigated 86 erythromycin-resistant S. pneumoniae strains isolated from respiratory (n=74) or non-respiratory (n=12) samples in Tunisia. Antimicrobial susceptibility was tested using the disk diffusion method. Macrolide-resistant strains were analysed by polymerase chain reaction (PCR) for ermA, ermB, mefA and msrD. We also investigated the macrolide resistance mechanisms in eight isolates (9.3%) by sequencing the L4 and L22 riboprotein-coding genes, plus relevant segments of the three 23S rRNA genes. Capsular serotypes were detected by multiplex PCR. Sequence types (STs) were explored using multilocus sequence typing (MLST).Results. Among the 86 studied strains, 70 (81.4 %) were resistant to penicillin G. The prevalent serotypes were 19F, 14, 19A and 23F. We observed that the cMLSB phenotype (66/86, 76.7%) was the most common in these pneumococci. In addition, ermB was the most frequent resistance gene. No mutation in ribosomal protein L22 or L4 or 23S rRNA was detected. Overall, 44 STs were identified in this study, including 16 that were described for the first time. Resistance to lincomycin, tetracycline and trimethoprim/sulfamethoxazole was observed in 55 (64 %), 34 (39.5 %) and 31 (36 %) isolates, respectively. Furthermore, an increase in fluoroquinolone use in particular may lead to the emergence of levofloxacin-resistant strains. Multidrug resistance was observed in 83 isolates (96.5%). Three global antibiotic-resistant clones were identified: Denmark14 ST230, Portugal19F ST177 and Spain9V ST156.Conclusion. This study shows that macrolide resistance among S. pneumoniae isolated in Tunisia is mainly related to target site modification. Our observations demonstrate a high degree of genetic diversity and capsular types among strains resistant to macrolides.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Macrolídeos/farmacologia , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Fenótipo , Streptococcus pneumoniae/classificação , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/isolamento & purificação , Tunísia
5.
PLoS One ; 15(3): e0230753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218595

RESUMO

Rabbits (Oryctolagus cuniculi) are very popular as pets. However, problems of otitits caused by Psoroptes cuniculi are one of the main reasons to visit the veterinarian. Isoxazolines are an alternative treatment to treat this mite, and therefore, an evaluation of the effectiveness of oral afoxalaner with milbemycin oxime in rabbits infected with P. cuniculi was carried out. Nineteen rabbits, of New Zealand breed, with otitis due to an infection with P. cuniculi, were treated, whereas six rabbits were left untreated and formed the control group. The ear canals of each individual were examined, through the collection of otic exudate samples with cotton swabs. These were visualized under the microscope to identify the ectoparasite. Each animal was treated with a single oral dose of 2.50 mg / kg of afoxolaner, and 0.50 mg / kg of milbemycin oxime. Clinical signs and lesions associated with the infection, such as the presence of detritus, cerumen and / or scabs, and erythema, were evaluated. After receiving the treatment, all the lesions were classified as: mild, moderate and intense, with a visual analog scale. A week after providing medication, there was a decrease in the lesions of the group treated with Nexgard Spectra®, without further topical or systemic treatment. The decrease was gradual in the treated group and no recurrence was detected of P. cuniculi infection in both ears. Thus, the administration of a single oral dose of afoxolaner with milbemycin oxime was effective for the treatment of P. cuniculi infection in rabbits.


Assuntos
Isoxazóis/farmacologia , Macrolídeos/farmacologia , Infestações por Ácaros/tratamento farmacológico , Naftalenos/farmacologia , Psoroptidae/fisiologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Isoxazóis/uso terapêutico , Macrolídeos/uso terapêutico , Naftalenos/uso terapêutico , Coelhos
6.
J Med Microbiol ; 69(3): 443-450, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32011228

RESUMO

Introduction. Pharyngotonsillitis caused by Streptococcus pyogenes (group A streptococci, or GAS) is among the most common infections treated with antibiotics in pediatric patients.Aim. This study aimed to analyse changes in molecular epidemiology and antibiotic susceptibility among GAS isolates in three study periods spanning 10 years.Methodology. GAS isolated from paediatric patients with pharyngotonsillitis during Period I (mid-2007 to 2008, n=235), Period II (2012, n=210), and Period III (2018, n=189) were analysed for emm type, multilocus sequence type (MLST), antibiotic susceptibility, and macrolide (ML)- and quinolone (QL)-resistance genes.Results. Over 20 % of isolates represented emm1 and emm12 types, remaining common in all three periods. Among other emm types, emm4 was common in Period I, emm28 and emm89 in Period II, and emm3 and emm89 in Period III. All isolates remained highly susceptible to penicillins and cephalosporins. Isolates possessing mefA, ermA, or ermB genes mediating ML resistance increased from 34.9 % in Period I to 60.9 % in Period II, but fell to 27.5 % in Period III. QL-resistant isolates with amino acid substitutions affecting ParC and/or GyrA gradually increased from 11.5 to 14.3 %. Specific sequence types identified by MLST and emm typing were associated closely with ML or QL resistance.Conclusion. Our findings indicate that even in ambulatory care, antibiotic choice for these infections should be based on rapid identification and characterization of causative pathogens.


Assuntos
Antibacterianos/farmacologia , Antígenos de Bactérias/genética , Farmacorresistência Bacteriana/genética , Infecções Estreptocócicas/epidemiologia , Streptococcus pyogenes/genética , Tonsilite/epidemiologia , Proteínas da Membrana Bacteriana Externa/genética , Técnicas de Tipagem Bacteriana , Criança , Pré-Escolar , Genótipo , Humanos , Japão/epidemiologia , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Tipagem de Sequências Multilocus , Nasofaringe/microbiologia , Filogenia , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes/classificação , Streptococcus pyogenes/efeitos dos fármacos , Tonsilite/tratamento farmacológico , Tonsilite/microbiologia
7.
PLoS One ; 15(2): e0228735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32032363

RESUMO

Influenza virus is an enveloped virus wrapped in a lipid bilayer derived from the host cell plasma membrane. Infection by influenza virus is dependent on these host cell lipids, which include sphingolipids. Here we examined the role of the sphingolipid, glucosylceramide, in influenza virus infection by knocking out the enzyme responsible for its synthesis, glucosylceramide synthase (UGCG). We observed diminished influenza virus infection in HEK 293 and A549 UGCG knockout cells and demonstrated that this is attributed to impaired viral entry. We also observed that entry mediated by the glycoproteins of other enveloped viruses that enter cells by endocytosis is also impaired in UGCG knockout cells, suggesting a broader role for UGCG in viral entry by endocytosis.


Assuntos
Glucosiltransferases/genética , Vírus da Influenza A/fisiologia , Células A549 , Sistemas CRISPR-Cas/genética , Edição de Genes , Glucosiltransferases/deficiência , Células HEK293 , Humanos , Macrolídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos
9.
Int J Antimicrob Agents ; 55(3): 105892, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926284

RESUMO

Three homologous oxygenated elansolid-type of polyketide spanned macrolides were isolated from a heterotrophic marine bacterium, Bacillus amyloliquefaciens MTCC 12716, associated with an intertidal red alga Hypnea valentiae. The complete genome of the bacterium was sequenced and all detectable natural product gene clusters were analysed. The B. amyloliquefaciens MTCC 12716 genome features polyketide synthase (pks) systems of every known formally classified family, nonribosomal peptide synthetases and hybrid clusters. Comprehensive spectroscopic studies revealed the compounds to possess isobenzofuranyl benzoate and 1H-furopyrano[2,3-c]oxacyclononadecine-6-carboxylate moieties. The identified compounds displayed broad-spectrum bactericidal activity against methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis, and drug-resistant strains of Pseudomonas aeruginosa and Klebsiella pneumoniae with minimum inhibitory concentrations (MICs) of ≤1.0 µg/mL, whereas the standard antibiotics ampicillin and chloramphenicol were active only at concentrations of ≥6.25 µg/mL. The plausible mechanism of elansolid-type macrolide biosynthesis by trans-AT polyketide synthases through the pks starter unit para-hydroxybenzoic acid was hypothesised, and the structures were correlated with the gene organisation, with the predicted gene cluster comprising 16 genes (~81 kb in size). The best binding poses for each compound with the peptide deformylase (PDF) protein of S. aureus revealed docking scores (>11.30 kcal/mol) greater than actinonin (6.96 kcal/mol), a natural PDF inhibitor. The higher electronic values along with optimum lipophilic parameters support the potential anti-infective properties of the studied macrolides. These antibacterial elansolid-type of polyketide spanned macrolides in marine symbiotic B. amyloliquefaciens could be potential leads for biotechnological and pharmaceutical applications against emerging multidrug-resistant pathogens.


Assuntos
Anti-Infecciosos/farmacologia , Bacillus amyloliquefaciens/química , Macrolídeos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Anti-Infecciosos/isolamento & purificação , Bacillus amyloliquefaciens/genética , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Macrolídeos/química , Macrolídeos/isolamento & purificação , Oxigênio
10.
J Med Microbiol ; 69(2): 244-248, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31958047

RESUMO

Introduction. Mycoplasma genitalium is a sexually transmitted organism with high levels of resistance to the recommended first-line therapy, azithromycin. The ResistancePlus MG test concurrently detects M. genitalium, and the presence of macrolide-resistance mutations (MRM). European, UK and Australian guidelines recommend a diagnostic test that reports MRM to optimize treatment through resistance-guided therapy. Hence, for samples collected for use on other platforms, reflex testing using the ResistancePlus MG test would be beneficial.Aim. To validate the ResistancePlus MG assay using samples collected in Aptima buffer for testing on the Hologic Panther.Methodology. Positive (n=99) and negative (n=229) clinical samples collected in Aptima buffer were extracted on the MagNA Pure 96 (Roche Diagnostics), and tested with the ResistancePlus MG test on the LightCycler 480 II (Roche Diagnostics). Results were compared to matched samples collected using standard sample collection (urine or swab resuspended in PBS), with positive percent agreement (PPA), negative percent agreement (NPA) and Cohen's Kappa statistic.Results. The ResistancePlus MG test had high performance with a 200 µl input volume (PPA/NPA for M. genitalium detection, 92.9 % [95 % confidence interval (CI): 85.5-96.9]/100 % [95 % CI: 97.9-100], MRM detection, 96.9 % [95 % CI: 88.2-99.5]/85.7 % [95 % CI: 66.4-95.3]) and for 1 ml input volume (PPA/NPA for M. genitalium detection, 95.9%/96.6%, MRM detection, 98.4%/90.3%). Samples remained positive after storage at room temperature beyond the manufacturer-recommended storage of <60 days (mean storage time for 1 ml extraction: 129 days).Conclusion. Samples collected using Aptima collection kits are suitable for reflex testing using the ResistancePlus MG test, allowing detection of macrolide resistance.


Assuntos
Antibacterianos/farmacologia , Testes Diagnósticos de Rotina/métodos , Farmacorresistência Bacteriana , Infecções por Mycoplasma/microbiologia , Mycoplasma genitalium/efeitos dos fármacos , Mycoplasma genitalium/isolamento & purificação , Austrália , Testes Diagnósticos de Rotina/instrumentação , Humanos , Macrolídeos/farmacologia , Infecções por Mycoplasma/diagnóstico , Mycoplasma genitalium/genética , Kit de Reagentes para Diagnóstico , Manejo de Espécimes
11.
Nat Commun ; 11(1): 140, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919415

RESUMO

Antimicrobial resistance is a major global threat that calls for new antibiotics. Globomycin and myxovirescin are two natural antibiotics that target the lipoprotein-processing enzyme, LspA, thereby compromising the integrity of the bacterial cell envelope. As part of a project aimed at understanding their mechanism of action and for drug development, we provide high-resolution crystal structures of the enzyme from the human pathogen methicillin-resistant Staphylococcus aureus (MRSA) complexed with globomycin and with myxovirescin. Our results reveal an instance of convergent evolution. The two antibiotics possess different molecular structures. Yet, they appear to inhibit identically as non-cleavable tetrahedral intermediate analogs. Remarkably, the two antibiotics superpose along nineteen contiguous atoms that interact similarly with LspA. This 19-atom motif recapitulates a part of the substrate lipoprotein in its proposed binding mode. Incorporating this motif into a scaffold with suitable pharmacokinetic properties should enable the development of effective antibiotics with built-in resistance hardiness.


Assuntos
Ácido Aspártico Endopeptidases/metabolismo , Proteínas de Bactérias/metabolismo , Macrolídeos/metabolismo , Staphylococcus aureus Resistente à Meticilina/enzimologia , Peptídeos/metabolismo , Sítios de Ligação/fisiologia , Membrana Celular/efeitos dos fármacos , Cristalografia por Raios X , Farmacorresistência Bacteriana/genética , Farmacorresistência Bacteriana/fisiologia , Macrolídeos/farmacologia , Peptídeos/farmacologia , Ligação Proteica/fisiologia , Estrutura Terciária de Proteína
12.
Chem Commun (Camb) ; 56(10): 1529-1532, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-31922172

RESUMO

The aplyronines are a family of highly cytotoxic marine natural products with potential application in targeted cancer chemotherapy. To address the severe supply issue, function-oriented molecular editing of their macrolactone scaffold led to the design of a series of simplified aplyronine analogues. Enabled by a highly convergent aldol-based route, the total synthesis of four analogues was achieved, with a significant improvement in step economy versus previous compounds, and their cancer cell growth inhibition in the HeLa cell line was determined. The modular strategy presented offers a means for significantly shortening their chemical synthesis to facilitate the continued development of this promising class of anticancer agent.


Assuntos
Antineoplásicos/síntese química , Macrolídeos/química , Proliferação de Células/efeitos dos fármacos , Células HeLa , Humanos , Macrolídeos/farmacologia , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade
13.
Paediatr Drugs ; 22(2): 217-228, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31939108

RESUMO

INTRODUCTION: The role of macrolides for treatment of children with acute asthma or wheezing exacerbations is unclear. OBJECTIVE: The aim of this systematic review was to evaluate the effectiveness of macrolides in children with recurrent wheezing presenting with acute asthma or wheezing exacerbation. METHODS: We conducted an electronic search in MEDLINE, EMBASE, CINAHL, LILACS, CENTRAL, and ClinicalTrials.gov. STUDY SELECTION CRITERIA: Randomized controlled trials of macrolides (any macrolide) compared with placebo or standard treatment in children up to 18 years with recurrent wheezing/asthma presenting with an acute exacerbation. OUTCOMES: Primary outcomes were need for hospitalization and/or time of acute asthma/wheezing symptoms resolution; secondary outcomes were duration of stay in the emergency department (ED)/clinic, severity of symptoms of the index episode, use of additional systemic corticosteroids or short active ß-2 agonists, changes in lung function measures, ED visit/hospitalization during first week after index episode, time to next exacerbation, or adverse effects (AEs). RESULTS: Only three studies met the inclusion criteria (n = 334 children, 410 treated episodes); two studies included recurrent wheezers and the third included asthmatic children. There was no difference in hospitalization between groups, but children treated with macrolides had a significantly lower time to symptoms resolution than controls, although the magnitude of benefit remains to be quantified due to no normal distribution data presented. There was no difference in time to next episode of exacerbation (HR 0.96; 95% CI 0.71-1.28; I2 = 0%; p = 0.77). In one study, children receiving macrolides had a significant decrease in the severity of symptoms, decrease use of salbutamol, and another study showed improved lung function. No study evaluated antibiotic resistance development. CONCLUSIONS: Limited evidence support that a macrolide trial could be considered in children with acute asthma or recurrent wheezing exacerbation.


Assuntos
Antiasmáticos/uso terapêutico , Antibacterianos/uso terapêutico , Asma/tratamento farmacológico , Macrolídeos/uso terapêutico , Sons Respiratórios/efeitos dos fármacos , Doença Aguda , Corticosteroides/uso terapêutico , Antiasmáticos/farmacologia , Antibacterianos/farmacologia , Criança , Humanos , Macrolídeos/farmacologia
14.
Chemosphere ; 247: 125795, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31927181

RESUMO

The association of low concentrations of pyriproxyfen and Spinosad, a naturally-occurring insecticide, was evaluated as an environment-friendly strategy to rationalize Aedes aegypti control programs by reducing larvicide consumption, saving financial costs and increasing residual effect against mosquitoes development. Firstly, the ecotoxicological parameters of the mixture was performed on non-target species Daphnia magna and the results confirmed that the low concentrations used in this larvicide mixture were not able to alter the reproductive parameters of chronically exposed microcrustaceans. In contrast, the mixture altered the behavior and development of Aedes aegypti, effectively inhibiting the emergence of adult insects for a long period. The results confirm the hypothesis that even at very low concentrations, the combination of the Spinosad and Pyriproxyfen larvicides offers an opportunity for Aedes aegypti public control programs to be more efficient.


Assuntos
Aedes/efeitos dos fármacos , Inseticidas/farmacologia , Macrolídeos/farmacologia , Controle de Mosquitos/métodos , Piridinas/farmacologia , Animais , Daphnia/efeitos dos fármacos , Combinação de Medicamentos , Ecotoxicologia/métodos , Larva/efeitos dos fármacos , Larva/crescimento & desenvolvimento
16.
Proc Natl Acad Sci U S A ; 117(4): 1971-1975, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932436

RESUMO

While most of the ribosome-targeting antibiotics are bacteriostatic, some members of the macrolide class demonstrate considerable bactericidal activity. We previously showed that an extended alkyl-aryl side chain is the key structural element determining the macrolides' slow dissociation from the ribosome and likely accounts for the antibiotics' cidality. In the nontranslating Escherichia coli ribosome, the extended side chain of macrolides interacts with 23S ribosomal RNA (rRNA) nucleotides A752 and U2609, that were proposed to form a base pair. However, the existence of this base pair in the translating ribosome, its possible functional role, and its impact on the binding and cidality of the antibiotic remain unknown. By engineering E. coli cells carrying individual and compensatory mutations at the 752 and 2609 rRNA positions, we show that integrity of the base pair helps to modulate the ribosomal response to regulatory nascent peptides, determines the slow dissociation rate of the extended macrolides from the ribosome, and increases their bactericidal effect. Our findings demonstrate that the ability of antibiotics to kill bacterial cells relies not only on the chemical nature of the inhibitor, but also on structural features of the target.


Assuntos
Antibacterianos/farmacologia , Escherichia coli/crescimento & desenvolvimento , Macrolídeos/farmacologia , RNA Ribossômico 23S/química , RNA Ribossômico 23S/metabolismo , Ribossomos/metabolismo , Antibacterianos/química , Pareamento de Bases , Sítios de Ligação , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Macrolídeos/química , Conformação de Ácido Nucleico , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , RNA Ribossômico 23S/genética
17.
Int J Cancer ; 146(6): 1652-1666, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31180579

RESUMO

Viruses can inhibit host autophagy through multiple mechanisms, and evasion of autophagy plays an important role in immune suppression and viral oncogenesis. Merkel cell polyomavirus (MCPyV) T-antigens are expressed and involved in the pathogenesis of a large proportion of Merkel cell carcinoma (MCC). Yet, how MCPyV induces tumorigenesis is not fully understood. Herein, we show that MCPyV T-antigens induce miR-375, miR-30a-3p and miR-30a-5p expressions, which target multiple key genes involved in autophagy, including ATG7, SQSTM1 (p62) and BECN1. In MCC tumors, low expression of ATG7 and p62 are associated with MCPyV-positive tumors. Ectopic expression of MCPyV small T-antigen and truncated large T-antigen (LT), but not the wild-type LT, resulted in autophagy suppression, suggesting the importance of autophagy evasion in MCPyV-mediated tumorigenesis. Torin-1 treatment induced cell death, which was attenuated by autophagy inhibitor, but not pan-caspase inhibitor, suggesting a potential role of autophagy in promoting cell death in MCC. Conceptually, our study shows that MCPyV oncoproteins suppress autophagy to protect cancer cells from cell death, which contribute to a better understanding of MCPyV-mediated tumorigenesis and potential MCC treatment.


Assuntos
Carcinoma de Célula de Merkel/virologia , Poliomavírus das Células de Merkel/metabolismo , MicroRNAs/biossíntese , Neoplasias Cutâneas/virologia , Antígenos Virais de Tumores/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Proteína 7 Relacionada à Autofagia/biossíntese , Proteína 7 Relacionada à Autofagia/genética , Proteína Beclina-1/biossíntese , Proteína Beclina-1/genética , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/genética , Carcinoma de Célula de Merkel/patologia , Linhagem Celular Tumoral , Humanos , Macrolídeos/farmacologia , MicroRNAs/genética , MicroRNAs/metabolismo , Naftiridinas/farmacologia , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/metabolismo , Infecções por Polyomavirus/patologia , Infecções por Polyomavirus/virologia , Processamento Pós-Transcricional do RNA , Proteína Sequestossoma-1/biossíntese , Proteína Sequestossoma-1/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia
18.
Chemistry ; 26(13): 2780-2792, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31667915

RESUMO

The nargenicin family of antibiotic macrolides comprise a group of bacterial natural products with a rare ether bridged cis-decalin moiety and a narrow spectrum of activity. Most family members were identified almost four decades ago and were placed on the shelf due to the numbers of broad-spectrum compounds available at the time. However, in light of rising rates of antimicrobial resistance, there has been a renewed interest in the use of narrow-spectrum antimicrobials. Here, we review the history of this family of compounds, including synthetic approaches, and highlight the recently uncovered genetic basis for nargenicin production. Given the renewed pharmaceutical interest in these compounds, we also investigate structure-activity relationships among these molecules, with a view to the future development of members of this unusual antibiotic family.


Assuntos
Antibacterianos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Lactonas/química , Macrolídeos/farmacologia , Antibacterianos/química , Hidrocarbonetos Aromáticos com Pontes/química , Humanos , Macrolídeos/química , Naftalenos , Relação Estrutura-Atividade
19.
Nat Prod Res ; 34(5): 710-713, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30445822

RESUMO

The correlation between the allocation of trisoxazole macrolides in the capitums, appendages, and bases of the sponge Penares cf. nux and the surface-attached bacteria on the corresponding parts was examined. The kabiramide contents were highest in the capitums, followed by the appendages and bases. Conversely, direct counts of cultivable surface-attached bacteria showed that the bacteria aggregate more densely on the surfaces of the bases. This suggested the repelling effects of the kabiramides against the fouling bacteria, particularly on the capitums and appendages. Twenty-two bacterial strains were isolated and identified to 15 species; however, none has shown the potentials as a producer of any secondary metabolites in the sponge P. nux.


Assuntos
Antibacterianos/metabolismo , Macrolídeos/farmacologia , Poríferos/metabolismo , Animais , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Aderência Bacteriana/fisiologia , Macrolídeos/metabolismo , Oxazóis/metabolismo , Oxazóis/farmacologia , Poríferos/química
20.
Parasitol Int ; 74: 101917, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31004804

RESUMO

In the present study, the larvicidal activity of ageing aqueous suspensions of spinosad against larvae of Culex pipiens biotype molestus, as well as their effect on the oviposition preferences of adult gravid females were evaluated in laboratory bioassays. Spinosad was applied at its label dose and the aqueous stock suspensions were stored for various ageing intervals up to 38 days. Untreated distilled water and diflubenzuron served as negative and positive control, respectively. Stock suspensions were taken after 0, 2, 6, 8, 16, 30 and 38 days of storage for diflubenzuron and after 0, 2, 6, 8, 20 and 27 days for spinosad, and were used for the bioassays. Furthermore, the effect of spinosad on the oviposition response of Cx. p. biotype molestus gravid females was investigated in two-choice oviposition preference bioassays. Spinosad was evaluated at half of its label dose and at its label dose, whereas diflubenzuron and distilled water served as positive and negative control, respectively. Results showed that both insecticides were found highly effective for the control of Cx. p. biotype molestus larvae, for ageing intervals up to 27 and 38 days for spinosad and diflubenzuron, respectively. Spinosad acted immediately after the preparation of the insecticidal solution (LT50 = 1.5 h), whereas for aged samples, LT50 values increased with the increase of the ageing interval (LT50 = 5 days for the 27 days old sample). For diflubenzuron, ageing time increased its insecticidal activity, as for aged diflubenzuron-treated solutions, lower LT50 values were achieved. In the oviposition preference bioassays, significantly fewer egg rafts were laid in water treated with spinosad at its label dose compared to control. However, this was not the case for water treated with spinosad at half of its label dose. Oviposition Activity Index (OAI) values were always comprised between -0.3 and 0.3, showing no relevant oviposition deterrence or attraction. The results of the present study contribute to our understanding of the effect of ageing on insecticidal solutions widely used in urban areas to control Cx. p. biotype molestus. Although an important vector of high public health importance, Cx. p. biotype molestus has been scarcely studied as target of environmentally and toxicologically reduced risk insecticides, such as spinosad.


Assuntos
Quitina/antagonistas & inibidores , Culex , Inseticidas/farmacologia , Macrolídeos/farmacologia , Oviposição/efeitos dos fármacos , Animais , Bioensaio , Quitina/biossíntese , Combinação de Medicamentos , Feminino , Larva , Mosquitos Vetores
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