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1.
BMC Nephrol ; 22(1): 83, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33691640

RESUMO

BACKGROUND: Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. CASE PRESENTATION: In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband's mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. CONCLUSIONS: Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

2.
J Asian Nat Prod Res ; : 1-9, 2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32924591

RESUMO

One new virginiamycin derivative, 'beilunmycin' (1), and three known virginiamycin antibiotics, 16-hydroxy-virginiamycin M1 (2), virginiamycin M2 (3), and virginiamycin M1 (4), were isolated from the culture of a mangrove-derived endophytic Streptomyces sp. 2BBP-J2. The structures were characterized on the basis of their spectroscopic data, and the absolute configuration of 1 was established by ECD calculations. Compounds 1-4 exhibited antibacterial activities against Gram-positive bacteria, with MIC values in the range of 0.5-16 µg/ml. All the compounds demonstrated strong protein translation-stalling activity, with minimal concentrations detected with pDualrep2 in the range of 1.9-5.9 nmol.

3.
J Infect Dev Ctries ; 14(6): 606-613, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32683351

RESUMO

INTRODUCTION: The clinical and molecular characteristics of hypervirulent Klebsiella pneumoniae (hvKp) in various provinces of China have been reported, however, there have been few reports in Hebei Province, North China. METHODOLOGY: The hvKp was identified by PCR amplification of hypervirulence-related genes, the hypermucoviscous phenotype was determined by the "string test", the drug susceptibility analysis was performed using the VITEK® 2 Compact Bacterial Identification and Monitoring System. Logistic regression was used to identify risk factors for hvKp infection. The molecular epidemiological characteristics of the strains were analyzed by pulsed-field gel electrophoresis (PFGE), and the capsular serotype of hvKp strain was detected by PCR. RESULTS: Overall, 52.21% (59/113) of K. pneumoniae isolates were hvKp, and the ratios of patients with older ages or a higher PMN cell count among hvKp infection were higher than those among classical Klebsiella pneumoniae (cKp) infection. hvKp are more susceptible to antibacterial drugs than cKp, and one ESBLs-producing hvKp strain was detected. The main capsular serotype of hvKp were K2, K57 and K1. PFGE indicated that the 59 strains of hvKp could be classified into 51 PFGE band types, forming 6 PFGE clusters. CONCLUSIONS: In this study, the detection rate of hvKp was 52.21% (59/113) identified by virulence genes. People with older ages or a higher PMN cell count are more likely to gain hvKp infection. ESBLs-producing hvKp is emerging, indicating the importance of epidemiologic surveillance and clinical awareness of this pathogen in this region.

4.
Opt Express ; 28(8): 11144-11155, 2020 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-32403631

RESUMO

Nonlinear optical effects in integrated microcavities have been studied extensively with the advantages of strong light-matter interaction, great scalability, and stability due to the small mode volume. However, the pump lasers stimulating nonlinear effects impose obstacles for practical applications, since the material absorption causes thermal resonance drift and instability. Here we experimentally demonstrate an all-optical control of the thermal behavior in optical microcavities for tunable doubly-resonant second-harmonic (SH) generation on an integrated photonic chip. Through an auxiliary control laser, the temperature of a selected microring can be efficiently changed, thus allowing precise frequency tuning of the doubly-resonant wavelength while eliminating the distortion of the lineshape induced by the thermo-optic effect. Although the phase-matching conditions will limit the tuning range of 55GHz, the technique is still potential to achieve a larger tuning range in combination with temperature regulation. Additionally, this approach has the advantage of quick reconfiguration, showing a fast modulation rate up to about 256 kHz. The theoretical model behind our experimental scheme is universal and applicable to other microcavity-enhanced nonlinear optical processes, and our work paves the way for controlling and utilizing the thermal effect in the applications of microcavities.

5.
ACS Infect Dis ; 6(7): 1796-1806, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32330004

RESUMO

Twenty-three polymyxin analogs with variations at nine amino acid positions were synthesized and assessed for antimicrobial activity and renal cytotoxicity. Compounds M2, 14, S2, and 16 (MIC = 0.125-4 µg/mL) had similar or stronger activities against susceptible and drug-resistant strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii compared to polymyxin B (MIC = 1-2 µg/mL). Most synthesized compounds (50% cytotoxic concentration, CC50 ≥ 200 µg/mL) exhibited lower cytotoxicity than polymyxin B (CC50 = 99 ± 6 µg/mL). Polymyxin S2 showed high plasma stability in vitro and strong efficacy in a mouse systemic infection model (ED50 = 0.9 mg/kg) against NDM-1-producing Klebsiella pneumoniae, suggesting that it is a potential candidate for drug development. The activity and cytotoxicity results indicated that the amino acids at positions 2, 3, 6, and 7 might be replaced. Effects on activity and cytotoxicity linked to changes in the number of positively charged amino acids varied among different cyclopeptide skeletons, but the underlying mechanisms are unknown.

6.
PLoS One ; 15(2): e0228797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32074133

RESUMO

(E)-N,N-dimethyl-4-oxo-4-(4-(pyridin-4-yl)phenyl)but-2-enamide hydrochloride (IMB-YH-4py5-2H) is a novel Protein Kinase B (PknB) inhibitor with potent activity against Mycobacterium tuberculosis strains. In the present study, a sensitive and specific liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine IMB-YH-4py5-2H in rat plasma. Sample pretreatment was achieved by liquid-liquid extraction with ethyl acetate, and separation was performed on an XTerra MS C18 column (2.1×50 mm, 3.5 µm) with gradient elution (methanol and 0.1% formic acid) at a flow rate of 0.3 mL/min. Detection was performed in multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over a concentration range of 1-100 ng/mL. The intra-day and inter-day precisions were lower than 8.46%, and the accuracies ranged from -8.71% to 12.36% at all quality control levels. The extraction recoveries were approximately 70%, and the matrix effects were negligible. All quality control samples were stable under different storage conditions. The validated method was successfully applied to a preclinical pharmacokinetic study in Sprague-Dawley rats. IMB-YH-4py5-2H demonstrated improved pharmacokinetic properties (higher exposure level) compared with its leading compound. IMB-YH-4py5-2H was also distributed throughout the lung pronouncedly, especially inside alveolar macrophages, indicating its effectiveness against lower respiratory infections.


Assuntos
Análise Química do Sangue/métodos , Cromatografia Líquida/métodos , Limite de Detecção , Piridinas/sangue , Piridinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Antituberculosos/sangue , Antituberculosos/isolamento & purificação , Antituberculosos/farmacocinética , Piridinas/isolamento & purificação , Ratos , Ratos Sprague-Dawley
7.
Bioorg Chem ; 94: 103487, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31831161

RESUMO

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 µg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a ß-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight ß-lactamase-producing resistant Gram-negative bacteria.

8.
PLoS One ; 14(6): e0217573, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170198

RESUMO

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen.


Assuntos
Gemifloxacina/análise , Gemifloxacina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Microdiálise , Músculos/efeitos dos fármacos , Músculos/microbiologia , Espectrometria de Massas em Tandem , Animais , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida , Ciprofloxacino/química , Ciprofloxacino/farmacologia , Modelos Animais de Doenças , Gemifloxacina/química , Gemifloxacina/farmacocinética , Masculino , Ligação Proteica , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Coxa da Perna/microbiologia , Distribuição Tecidual
9.
Opt Express ; 27(5): 6660-6671, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30876246

RESUMO

Cavity-enhanced optical controlling is experimentally observed with a low-control laser power in a cavity-atom ensemble system. Here, the three-level atoms are coupled with two optical modes of a Fabry-Perot cavity, where a new theoretical model is developed to describe the effective three-wave mixing process between spin-wave and optical modes. By adjusting either temperature or cavity length, we demonstrate the precise frequency tuning of the hybrid optical-atomic resonances. When the doubly-resonant condition is satisfied, the probe laser can be easily modulated by a control laser. In addition, interesting non-Hermitian physics are predicted theoretically and demonstrated experimentally, and all-optical switching is also achieved. Such a doubly-resonant cavity-atom ensemble system without a specially designed cavity can be used for future applications, such as optical signal storage and microwave-to-optical frequency conversion.

10.
Opt Lett ; 44(5): 1150-1153, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30821735

RESUMO

To extend the coherence of quantum transitions for laser locking, as well as increase the compactness and stability of the experimental setup, we propose to utilize photonic integrated resonators with high second-harmonic (SH) generation efficiencies as reliable frequency doublers that link the desired frequencies with the frequency references. In this Letter, a sufficiently strong SH signal up to microwatts was generated by a photonic integrated frequency doubler using a milliwatt infrared (IR) laser source. Furthermore, an increased SH generation bandwidth covering Rb85 and Rb87D2 transition lines, as well as saturated absorption spectroscopy, was demonstrated by tuning the pump power and chip temperature. Here we present, to the best of our knowledge, the first successful locking of an IR laser to Rb saturated absorption lines via a photonic chip frequency doubler.

11.
Molecules ; 24(5)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862066

RESUMO

Twenty-five new derivatives of 8-hydroxycycloberberine (1) were synthesized and evaluated for their activities against Gram-positive bacteria, taking 1 as the lead. Part of them displayed satisfactory antibacterial activities against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-intermediate Staphylococcus aureus (VISA). Especially, compound 15a displayed an excellent anti-MRSA activity with MICs (minimum inhibitory concentrations) of 0.25⁻0.5 µg/mL, better than that of 1. It also displayed high stability in liver microsomes and whole blood, and the LD50 value of over 65.6 mg·kg-1 in mice via intravenous route, suggesting a good druglike feature. The mode of action showed that 15a could effectively suppress topo IV-mediated decatenation activity at the concentration of 7.5 µg/mL, through binding a different active pocket of bacterial topo IV from quinolones. Taken together, the derivatives of 1 constituted a promising kind of anti-MRSA agents with a unique chemical scaffold and a specific biological mechanism, and compound 15a has been chosen for the next investigation.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Berberina/química , Berberina/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Berberina/análogos & derivados , DNA Topoisomerase IV/antagonistas & inibidores , DNA Topoisomerase IV/química , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
12.
Molecules ; 24(3)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717338

RESUMO

Nineteen new quinoline derivatives were prepared via the Mannich reaction and evaluated for their antibacterial activities against both Gram-positive (G⁺) and Gram-negative (G-) bacteria, taking compound 1 as the lead. Among the target compounds, quinolone coupled hybrid 5d exerted the potential effect against most of the tested G⁺ and G- strains with MIC values of 0.125⁻8 µg/mL, much better than those of 1. Molecular-docking assay showed that compound 5d might target both bacterial LptA and Top IV proteins, thereby displaying a broad-spectrum antibacterial effect. This hybridization strategy was an efficient way to promote the antibacterial activity of this kind, and compound 5d was selected for the further investigation, with an advantage of a dual-target mechanism of action.


Assuntos
Antibacterianos/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Quinolinas/química , Antibacterianos/síntese química , Antibacterianos/farmacologia , Proteínas de Transporte/química , Proteínas de Escherichia coli/química , Bactérias Gram-Negativas/patogenicidade , Bactérias Gram-Positivas/patogenicidade , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Quinolinas/síntese química , Quinolinas/farmacologia , Relação Estrutura-Atividade
13.
Chem Biodivers ; 16(2): e1800560, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30467968

RESUMO

A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their in vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Diterpenos/química , Diterpenos/farmacologia , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Compostos Policíclicos , Relação Estrutura-Atividade , Sulfetos , Sulfóxidos
14.
Int J Antimicrob Agents ; 52(6): 799-804, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30194973

RESUMO

Transfer of aac(6')-aph(2″) transposons mediating high-level gentamicin resistance (HLGR) in Enterococcus faecalis is a serious problem in the clinic. However, factors affecting the transfer of aac(6')-aph(2″) have not yet been elucidated. The current study aimed to examine the genetic and molecular basis of HLGR in E. faecalis strains isolated in Beijing (China) and to clarify the relationship between transfer efficiency of aac(6')-aph(2″) transposons and the transposon structure/location. A total of five transposon structures were identified by PCR mapping of the corresponding transposon regions, including a Tn5281-like non-truncated transposon and four truncated transposons. A plasmid location study of aac(6')-aph(2″) by Southern blot following S1-PFGE and filter mating conjugation experiments demonstrated that plasmid location rates correlated with conjugation-positive rates. Chromosome walking to identify the sequence upstream of a representative type III truncated transposon found a truncated aph(2″)-Ia region, and further PCR analysis of this region among strains from different groups revealed similar a positive rate trend as the transposon plasmid location rate and conjugation-positive rate. In conclusion, aac(6')-aph(2″) transposons were of different structures in E. faecalis strains from Beijing, with two new transposon structures that have not been reported elsewhere. Presence of the truncated aph(2″)-Ia region upstream of some truncated transposons suggests recombination between aminoglycoside-modifying enzyme genes. Possible links exist among plasmid location, conjugation and the presence of truncated aph(2″)-Ia upstream of the transposon.


Assuntos
Acetiltransferases/genética , Elementos de DNA Transponíveis , Farmacorresistência Bacteriana , Enterococcus faecalis/genética , Transferência Genética Horizontal , Infecções por Bactérias Gram-Positivas/microbiologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Antibacterianos/farmacologia , Pequim , Mapeamento Cromossômico , Conjugação Genética , Enterococcus faecalis/classificação , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/isolamento & purificação , Variação Genética , Gentamicinas/farmacologia , Humanos , Plasmídeos/análise , Reação em Cadeia da Polimerase
15.
Eur J Med Chem ; 157: 877-886, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30145374

RESUMO

A series of new 13-substituted cycloberberine (CBBR) derivatives were prepared and evaluated for their antibacterial activities against Gram-positive bacteria taking CBBR as the lead. Structure-activity relationship revealed that the introduction of a suitable electron-donating group at the 13-position in CBBR might be beneficial for the antibacterial potency. Among them, compounds 5b and 5w exhibited high potency against methicillin-sensitive (MSSA) and resistant strains of S. aureus (MRSA) with MIC values of 1-4 µg/mL. Both of them also displayed high stabilities in blood, and good in vivo safety profiles with LD50 values of 65.6 and 41.2 mg kg-1 in intravenous route respectively. Molecular docking analysis indicated that compound 5b might target FtsZ protein that could inhibit cell division, with the advantage of activity against multidrug resistant S. aureus. Therefore, we consider 13-substituted CBBR derivatives to be a novel class of anti-MRSA agents worthy of further investigation.


Assuntos
Antibacterianos/farmacologia , Berberina/envenenamento , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Berberina/síntese química , Berberina/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
16.
J Med Chem ; 61(5): 1845-1857, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29412662

RESUMO

In this paper, 26 natural polymyxin components and a new derivative S2 were synthesized, and their differences in efficacy and toxicity have been investigated. Almost all of the synthesized components showed strong activity against both susceptible and resistant strains of E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii. The toxicities were obviously different between the components. Only some of the components were tested for toxicity in vivo. Compounds E2, E2-Val, A2, M2, D2, and S2 showed obviously lower renal cytotoxicity and acute toxicity than polymyxins B and E. The in vivo nephrotoxicity of E2, M2, and S2 was similar to that of polymyxin E. Compound S2, with four positive charges, was especially interesting as it possessed both increased efficacy and decreased toxicity. The SAR and toxicity studies indicated that further structural modification could concentrate on polymyxin S. The results also indicated that S2 could be a new drug candidate.


Assuntos
Bactérias/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Polimixinas/toxicidade , Animais , Humanos , Fígado/efeitos dos fármacos , Peptídeos Cíclicos/química , Polimixinas/análogos & derivados , Polimixinas/síntese química , Relação Estrutura-Atividade , Testes de Toxicidade
17.
Shanghai Kou Qiang Yi Xue ; 26(2): 213-216, 2017 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-28815255

RESUMO

PURPOSE: To investigate the related risk factors of temporomandibular disorders(TMD), and to provide evidences for clinical prevention. METHODS: One hundred and nine TMD patients were included in the study as case group, while 109 people with no TMJ symptoms and signs were selected randomly as control group. All subjects fulfilled questionaires. Logistics regression analysis was used to analyze the data with SPSS 22.0 software package. RESULTS: Females patients were more common than males, with 20~29 age group accounting for 44%. The proportions of patients with habits of bruxism or clenching, unilateral mastication and maxillofacial injure history were significantly greater than those of control group (P<0.05). The proportions of patients with life stress and habits of stay-up late, chewing hard food and orthodontic treatment history showed no significant difference compared with the control group (P>0.05). CONCLUSIONS: TMD has a higher prevalence in female than in male, with a peak incidence in 20-29 age group. Habits of bruxism or clenching, unilateral mastication and maxillofacial injury history may be risk factors of TMD, while life stress, habits of stay-up late, chewing hard food and orthodontic treatments show no significant correlation with TMD.


Assuntos
Bruxismo , Transtornos da Articulação Temporomandibular/epidemiologia , Feminino , Humanos , Masculino , Mastigação , Prevalência , Fatores de Risco
18.
Molecules ; 21(11)2016 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-27886094

RESUMO

Two new amicoumacins, named Damxungmacin A (1) and B (2), were isolated from the culture broth of a soil-derived bacterium Bacillus subtilis XZ-7. Their chemical structures were elucidated by spectroscopic studies (UV, IR, NMR and HR-ESI-MS). Compound 1 possessed a 1,4-diazabicyclo[2.2.1]heptane-2-one ring system in its structure, which was reported for the first time, while 2 had a 1-acetylmorpholine-3-one moiety, which was naturally rare. Compound 1 exhibited moderate to weak cytotoxic activities against three human tumor cell lines (A549, HCT116 and HepG2) with IC50 values of 13.33, 14.34 and 13.64 µM, respectively. Meanwhile, compound 1 showed weak antibacterial activities against some strains of Staphylococcus epidermidis, while compound 2 at 16 µg/mL did not show antibacterial activity.


Assuntos
Antineoplásicos/farmacologia , Bacillus subtilis/química , Cumarínicos/isolamento & purificação , Cumarínicos/farmacologia , Células A549 , Antibacterianos/química , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Bacillus subtilis/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/química , Células HCT116 , Células Hep G2 , Humanos , Estrutura Molecular , Microbiologia do Solo , Staphylococcus epidermidis/efeitos dos fármacos
19.
Yao Xue Xue Bao ; 51(1): 105-9, 2016 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-27405170

RESUMO

Chuangxinmycin (CM) from Actinoplanes tsinanensis was an antibiotic discovered by Chinese scientists about 40 years ago. It contains a new heterocyclic system of indole fused with dihydrothiopyran, whose biosynthetic mechanism remains unclear. CM is used as an oral medicine in the treatment of bacterial infections in China. The simple structure makes CM as an attractive candidate of structure modification for improvement of antibacterial activity. Recently, we analyzed the secondary metabolites of Actinoplanes tsinanensis CPCC 200056, a CM producing strain, as a natural CM analogue. We discovered the first natural CM analogue 3-demethylchuangxinmycin (DCM) as a new natural product. Compared to CM, DCM exhibited a much weaker activity in the inhibition of the bacterial strains tested. The finding provides valuable information for the structure-activity relationship in the biosynthesis of CM.


Assuntos
Antibacterianos/isolamento & purificação , Micromonosporaceae/química , Antibacterianos/química , China , Indóis/química , Indóis/isolamento & purificação , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 110: 151-63, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26827160

RESUMO

A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 µg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 µg/mL to 8 µg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Monobactamas/química , Monobactamas/farmacologia , Antibacterianos/síntese química , Aztreonam/análogos & derivados , Aztreonam/síntese química , Aztreonam/farmacologia , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Monobactamas/síntese química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
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