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1.
Sci Rep ; 11(1): 10062, 2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33980996

RESUMO

Thienamycin, the first representative of carbapenem antibiotics was discovered in the mid-1970s from soil microorganism, Streptomyces cattleya, during the race to discover inhibitors of bacterial peptidoglycan synthesis. Chemically modified into imipenem (N-formimidoyl thienamycin), now one of the most clinically important antibiotics, thienamycin is encoded by a thienamycin gene cluster composed of 22 genes (thnA to thnV) from S. cattleya NRRL 8057 genome. Interestingly, the role of all thn-genes has been experimentally demonstrated in the thienamycin biosynthesis, except thnS, despite its annotation as putative ß-lactamase. Here, we expressed thnS gene and investigated its activities against various substrates. Our analyses revealed that ThnS belonged to the superfamily of metallo-ß-lactamase fold proteins. Compared to known ß-lactamases such as OXA-48 and NDM-1, ThnS exhibited a lower affinity and less efficiency toward penicillin G and cefotaxime, while imipenem is more actively hydrolysed. Moreover, like most MBL fold enzymes, additional enzymatic activities of ThnS were detected such as hydrolysis of ascorbic acid, single strand DNA, and ribosomal RNA. ThnS appears as a MBL enzyme with multiple activities including a specialised ß-lactamase activity toward imipenem. Thus, like toxin/antitoxin systems, the role of thnS gene within the thienamycin gene cluster appears as an antidote against the produced thienamycin.


Assuntos
Antibacterianos/farmacologia , Cefotaxima/farmacologia , Cefamicinas/farmacologia , Penicilina G/farmacologia , Streptomyces/efeitos dos fármacos , Tienamicinas/farmacologia , beta-Lactamases/metabolismo , Streptomyces/enzimologia
2.
Protein Pept Lett ; 28(2): 205-220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32707026

RESUMO

BACKGROUND: Streptomyces clavuligerus is prolific producer of cephamycin C, a medically important antibiotic. In our former study, cephamycin C titer was 2-fold improved by disrupting homoserine dehydrogenase (hom) gene of aspartate pahway in Streptomyces clavuligerus NRRL 3585. OBJECTIVE: In this article, we aimed to provide a comprehensive understanding at the proteome level on potential complex metabolic changes as a consequence of hom disruption in Streptomyces clavuligerus AK39. METHODS: A comparative proteomics study was carried out between the wild type and its hom disrupted AK39 strain by 2 Dimensional Electrophoresis-Matrix Assisted Laser Desorption and Ionization Time-Of-Flight Mass Spectrometry (2DE MALDI-TOF/MS) and Nanoscale Liquid Chromatography- Tandem Mass Spectrometry (nanoLC-MS/MS) analyses. Clusters of Orthologous Groups (COG) database was used to determine the functional categories of the proteins. The theoretical pI and Mw values of the proteins were calculated using Expasy pI/Mw tool. RESULTS: "Hypothetical/Unknown" and "Secondary Metabolism" were the most prominent categories of the differentially expressed proteins. Upto 8.7-fold increased level of the positive regulator CcaR was a key finding since CcaR was shown to bind to cefF promoter thereby direcly controlling its expression. Consistently, CeaS2, the first enzyme of CA biosynthetic pathway, was 3.3- fold elevated. There were also many underrepresented proteins associated with the biosynthesis of several Non-Ribosomal Peptide Synthases (NRPSs), clavams, hybrid NRPS/Polyketide synthases (PKSs) and tunicamycin. The most conspicuously underrepresented protein of amino acid metabolism was 4-Hydroxyphenylpyruvate dioxygenase (HppD) acting in tyrosine catabolism. The levels of a Two Component System (TCS) response regulator containing a CheY-like receiver domain and an HTH DNA-binding domain as well as DNA-binding protein HU were elevated while a TetR-family transcriptional regulator was underexpressed. CONCLUSION: The results obtained herein will aid in finding out new targets for further improvement of cephamycin C production in Streptomyces clavuligerus.


Assuntos
Proteínas de Bactérias/metabolismo , Cefamicinas/metabolismo , Homosserina Desidrogenase/deficiência , Proteoma/análise , Proteoma/metabolismo , Streptomyces/metabolismo , Espectrometria de Massas em Tandem/métodos , Antibacterianos/metabolismo , Regulação Bacteriana da Expressão Gênica , Homosserina Desidrogenase/genética , Streptomyces/genética , Streptomyces/crescimento & desenvolvimento
5.
Sci Rep ; 9(1): 12905, 2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501462

RESUMO

Cephamycin-associated hemorrhages have been reported since their launch. This research aimed to determine risk factors for cephamycin-associated hemorrhagic events and produce a risk scoring system using National Taiwan University Hospital (NTUH) database. Patients who were older than 20 years old and consecutively used study antibiotics for more than 48 hours (epidode) at NTUH between January 1st, 2009 and December 31st, 2015 were included. The population was divided into two cohorts for evaluation of risk factors and validation of the scoring system. Multivariate logistic regression was used for the assessment of the adjusted association between factors and the outcome of interest. Results of the multivariate logistic regression were treated as the foundation to develop the risk scoring system. There were 46402 and 22681 episodes identified in 2009-2013 and 2014-2015 cohorts with 356 and 204 hemorrhagic events among respective cohorts. Use of cephamycins was associated with a higher risk for hemorrhagic outcomes (aOR 2.03, 95% CI 1.60-2.58). Other risk factors included chronic hepatic disease, at least 65 years old, prominent bleeding tendency, and bleeding history. A nine-score risk scoring system (AUROC = 0.8035, 95% CI 0.7794-0.8275; Hosmer-Lemeshow goodness-of-fit test p = 0.1044) was developed based on the identified risk factors, with higher scores indicating higher risk for bleeding. Use of cephamycins was associated with more hemorrhagic events compared with commonly used penicillins and cephalosporins. The established scoring system, CHABB, may help pharmacists identify high-risk patients and provide recommendations according to the predictive risk, and eventually enhance the overall quality of care.


Assuntos
Antibacterianos/efeitos adversos , Cefamicinas/efeitos adversos , Hemorragia/epidemiologia , Hemorragia/etiologia , Idoso , Comorbidade , Feminino , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Curva ROC , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Taiwan/epidemiologia
6.
Nat Microbiol ; 4(12): 2237-2245, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31406331

RESUMO

Spore-forming bacteria encompass a diverse range of genera and species, including important human and animal pathogens, and food contaminants. Clostridioides difficile is one such bacterium and is a global health threat because it is the leading cause of antibiotic-associated diarrhoea in hospitals. A crucial mediator of C. difficile disease initiation, dissemination and re-infection is the formation of spores that are resistant to current therapeutics, which do not target sporulation. Here, we show that cephamycin antibiotics inhibit C. difficile sporulation by targeting spore-specific penicillin-binding proteins. Using a mouse disease model, we show that combined treatment with the current standard-of-care antibiotic, vancomycin, and a cephamycin prevents disease recurrence. Cephamycins were found to have broad applicability as an anti-sporulation strategy, as they inhibited sporulation in other spore-forming pathogens, including the food contaminant Bacillus cereus. This study could directly and immediately affect treatment of C. difficile infection and advance drug development to control other important spore-forming bacteria that are problematic in the food industry (B. cereus), are potential bioterrorism agents (Bacillus anthracis) and cause other animal and human infections.


Assuntos
Antibacterianos/farmacologia , Cefamicinas/farmacologia , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/prevenção & controle , Animais , Toxinas Bacterianas/genética , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Clostridioides difficile/genética , Clostridioides difficile/crescimento & desenvolvimento , Infecções por Clostridium/microbiologia , Modelos Animais de Doenças , Regulação Bacteriana da Expressão Gênica , Genes Bacterianos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Ligação às Penicilinas/efeitos dos fármacos , Proteínas de Ligação às Penicilinas/genética , Esporos Bacterianos/efeitos dos fármacos , Vancomicina/farmacologia , Células Vero/efeitos dos fármacos
7.
J Chromatogr Sci ; 57(3): 204-212, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30395207

RESUMO

Thirteen unknown impurities and isomers in cefminox sodium were separated and characterized by liquid chromatography coupled with high-resolution ion trap/time-of-flight mass spectrometry (LC-IT-TOF-MS) with the positive mode of electrospray ionization (ESI) method. New HPLC-gradient elution method was developed for the detection of impurities in cefminox sodium. And the ESI ion trap multiple-stage tandem mass spectrometry had been applied successfully to the direct investigation of impurities and isomers in cefminox sodium. The fragmentation patterns and structural assignment of these impurities were studied. Full scan liquid chromatography-mass spectrometry (LC-MS) was first performed to obtain the m/z value of the protonated molecules and formulas of all detected peaks, LC-MSn (n = 1-6) were then carried out on the compounds of interest. Structures of 13 degradation products in cefminox sodium were deduced based on the high-resolution MSn (n = 1-6) data, assisted by the UV spectra and stress testing. And the forming mechanisms of degradation products in cefminox were also studied. The method of LC-IT-TOF-MSn (n = 1-6) was worthy of widespread use and application for the further improvement of official monographs in pharmacopoeias with the advantages of stability and repeatability.


Assuntos
Cefamicinas/análise , Cefamicinas/química , Cromatografia Líquida/métodos , Contaminação de Medicamentos , Espectrometria de Massas por Ionização por Electrospray/métodos , Isomerismo
8.
Int J Antimicrob Agents ; 52(3): 421-424, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29944954

RESUMO

A clinical isolate of Citrobacter freundii (JA99) obtained from a bile culture of a Taiwanese patient was found to produce a plasmid-encoded ß-lactamase conferring resistance to oxyimino-cephalosporins and cephamycins. Resistance arising from production of the ß-lactamase could be transferred by conjugation with an IncW plasmid (pJA99) into Escherichia coli J53. The substrate and inhibition profiles of this enzyme resembled that of an AmpC ß-lactamase. The resistance gene of pJA99, cloned and expressed in E. coli DH5α, was shown to contain an open reading frame showing 92% amino acid identity with the plasmid-encoded enzyme CFE-1 of E. coli KU6400. DNA sequence analysis also identified a gene upstream of ampC in pJA99 whose sequence was 95.0% identical to the ampR gene from E. coli KU6400. In addition, orf1, the fumarate operon (frdABCD), blc, lolB and repB surrounding the ampR-ampC genes in C. freundii were identified. This DNA fragment was absent in other Citrobacter spp. Therefore, we describe a new plasmid-encoded AmpC ß-lactamase, named CFE-2. This study highlights the emergence of broad-spectrum cephalosporin resistance in C. freundii owing to a new type of AmpC ß-lactamase.


Assuntos
Proteínas de Bactérias/genética , Resistência às Cefalosporinas/genética , Cefalosporinase/genética , Citrobacter freundii/genética , Plasmídeos/genética , beta-Lactamases/genética , Cefalosporinas/farmacologia , Cefamicinas/farmacologia , Citrobacter freundii/efeitos dos fármacos , Citrobacter freundii/isolamento & purificação , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Humanos , Taiwan
9.
Clin Infect Dis ; 64(7): 972-980, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28362938

RESUMO

The continued rise in infections caused by extended-spectrum ß-lactamase (ESBL)-producing pathogens is recognized globally as one of the most pressing concerns facing the healthcare community. Carbapenems are widely regarded as the antibiotics of choice for the treatment of ESBL-producing infections, even when in vitro activity to other ß-lactams has been demonstrated. However, indiscriminant carbapenem use is not without consequence, and carbapenem overuse has contributed to the emergence of carbapenem-resistant Enterobacteriaceae. The use of non-carbapenem ß-lactams for the treatment of ESBL infections has yielded conflicting results. In this review, we discuss the available data for the use of cephamycins, cefepime, piperacillin-tazobactam, ceftolozane-tazobactam, and ceftazidime-avibactam for the treatment of ESBL infections.


Assuntos
Antibacterianos/uso terapêutico , Resistência beta-Lactâmica , Inibidores de beta-Lactamases/uso terapêutico , beta-Lactamases/genética , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Cefepima , Cefalosporinas/farmacologia , Cefalosporinas/uso terapêutico , Cefamicinas/farmacologia , Cefamicinas/uso terapêutico , Enterobacteriaceae/efeitos dos fármacos , Enterobacteriaceae/genética , Infecções por Enterobacteriaceae/tratamento farmacológico , Infecções por Enterobacteriaceae/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacologia , Ácido Penicilânico/uso terapêutico , Piperacilina/farmacologia , Piperacilina/uso terapêutico , Combinação Piperacilina e Tazobactam , Resultado do Tratamento , Resistência beta-Lactâmica/efeitos dos fármacos , Inibidores de beta-Lactamases/farmacologia
10.
Mol Ecol ; 26(12): 3217-3229, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28316142

RESUMO

Beta-lactam biosynthesis was thought to occur only in fungi and bacteria, but we recently reported the presence of isopenicillin N synthase in a soil-dwelling animal, Folsomia candida. However, it has remained unclear whether this gene is part of a larger beta-lactam biosynthesis pathway and how widespread the occurrence of penicillin biosynthesis is among animals. Here, we analysed the distribution of beta-lactam biosynthesis genes throughout the animal kingdom and identified a beta-lactam gene cluster in the genome of F. candida (Collembola), consisting of isopenicillin N synthase (IPNS), δ-(L-α-aminoadipoyl)-L-cysteinyl-D-valine synthetase (ACVS), and two cephamycin C genes (cmcI and cmcJ) on a genomic scaffold of 0.76 Mb. All genes are transcriptionally active and are inducible by stress (heat shock). A beta-lactam compound was detected in vivo using an ELISA beta-lactam assay. The gene cluster also contains an ABC transporter which is coregulated with IPNS and ACVS after heat shock. Furthermore, we show that different combinations of beta-lactam biosynthesis genes are present in over 60% of springtail families, but they are absent from genome- and transcript libraries of other animals including close relatives of springtails (Protura, Diplura and insects). The presence of beta-lactam genes is strongly correlated with an euedaphic (soil-living) lifestyle. Beta-lactam genes IPNS and ACVS each form a phylogenetic clade in between bacteria and fungi, while cmcI and cmcJ genes cluster within bacteria. This suggests a single horizontal gene transfer event most probably from a bacterial host, followed by differential loss in more recently evolving species.


Assuntos
Proteínas de Artrópodes/genética , Artrópodes/genética , Família Multigênica , beta-Lactamas , Animais , Artrópodes/enzimologia , Cefamicinas , Oxirredutases/genética , Peptídeo Sintases/genética , Filogenia
11.
Appl Environ Microbiol ; 83(1)2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27795309

RESUMO

Antimicrobial resistance through extended-spectrum beta-lactamases (ESBLs) and transferable (plasmid-encoded) cephamycinases (pAmpCs) represents an increasing problem in human and veterinary medicine. The presence of ESBL-/pAmpC-producing commensal enterobacteria in farm animals, such as broiler chickens, is considered one possible source of food contamination and could therefore also be relevant for human colonization. Studies on transmission routes along the broiler production chain showed that 1-day-old hatchlings are already affected. In this study, ESBL-/pAmpC-positive broiler parent flocks and their corresponding eggs, as well as various environmental and air samples from the hatchery, were analyzed. The eggs were investigated concerning ESBL-/pAmpC-producing enterobacteria on the outer eggshell surface (before/after disinfection), the inner eggshell surface, and the egg content. Isolates were analyzed concerning their species, their phylogroup in the case of Escherichia coli strains, the respective resistance genes, and the phenotypical antibiotic resistance. Of the tested eggs, 0.9% (n = 560) were contaminated on their outer shell surface. Further analyses using pulsed-field gel electrophoresis showed a relationship of these strains to those isolated from the corresponding parent flocks, which demonstrates a pseudo-vertical transfer of ESBL-/pAmpC-producing enterobacteria into the hatchery. Resistant enterobacteria were also found in environmental samples from the hatchery, such as dust or surfaces which could pose as a possible contamination source for the hatchlings. All 1-day-old chicks tested negative directly after hatching. The results show a possible entry of ESBL-/pAmpC-producing enterobacteria from the parent flocks into the hatchery; however, the impact of the hatchery on colonization of the hatchlings seems to be low. IMPORTANCE: ESBL-/pAmpC-producing enterobacteria occur frequently in broiler-fattening farms. Recent studies investigated the prevalence and possible transmission route of these bacteria in the broiler production chain. It seemed very likely that the hatcheries play an important role in transmission and/or contamination events. There are only few data on transmission investigations from a grandparent or parent flock to their offspring. However, reliable data on direct or indirect vertical transmission events in the hatchery are not available. Therefore, we conducted our study and intensively investigated the broiler hatching eggs from ESBL-/pAmpC-positive broiler parent flocks as well as the hatchlings and the environment of the hatchery.


Assuntos
Cefamicinas/metabolismo , Infecções por Enterobacteriaceae/veterinária , Escherichia coli/genética , Escherichia/genética , Transmissão Vertical de Doenças Infecciosas/veterinária , Doenças das Aves Domésticas/transmissão , beta-Lactamases/genética , Animais , Animais Domésticos , Galinhas/microbiologia , Farmacorresistência Bacteriana Múltipla/genética , Ovos/microbiologia , Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/transmissão , Escherichia/efeitos dos fármacos , Escherichia/enzimologia , Escherichia/isolamento & purificação , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/isolamento & purificação , Infecções por Escherichia coli/microbiologia , Infecções por Escherichia coli/transmissão , Infecções por Escherichia coli/veterinária , Fazendas , Humanos , Plasmídeos , Doenças das Aves Domésticas/microbiologia , beta-Lactamases/biossíntese
12.
J Pharm Biomed Anal ; 129: 28-33, 2016 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-27394175

RESUMO

A selective and reproducible HPLC-MS/MS method was developed and fully validated for the determination of cefbuperazone in human plasma and urine. Samples were prepared using protein precipitation and separated on a Zorbax Eclipse Plus C18 column (2.1×50mm, 3.5µm). The API-4000 mass spectrometer was operated under multiple reaction monitoring mode (MRM) using the electrospray ionization technique. Linearity was achieved from 0.250 to 250µg/mL in plasma and 20.0-5000µg/mL in urine. The method was successfully applied to a pharmacokinetic study of cefbuperazone in healthy Chinese volunteers after drip intravenous infusion of 0.5, 1.0, 2.0g cefbuperazone sodium injection. Cefbuperazone reached a maximum concentration (Cmax) of 44.7±8.1µg/mL, 86.7±12.7µg/mL and 168±14µg/mL in 0.5, 1.0 and 2.0g dose groups respectively, at 60min after the start of infusion. The half-life (t1/2) was between 1.8-1.9h, and the elimination constant (kel) was between 0.36-0.39h(-1). The results proved that cefbuperazone showed linear pharmacokinetic profile in the dose range of 0.5-2.0g without gender difference. Drug accumulation was not observed. Cefbuperazone reached the maximum excretion rate in urine 2h after the start of infusion. About 60.0% of the administered drug was excreted via urine as unchanged form within 12h. The cumulative excretion of cefbuperazone after single drip intravenous infusion was proportional to the administered dose within the range from 0.5g to 2.0g.


Assuntos
Grupo com Ancestrais do Continente Asiático , Cefamicinas/administração & dosagem , Cefamicinas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Adulto , Cromatografia Líquida de Alta Pressão/métodos , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Distribuição Aleatória , Voluntários , Adulto Jovem
13.
Int J Food Microbiol ; 223: 75-8, 2016 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-26915052

RESUMO

Although cefoperazone is the most commonly used antibiotic in Campylobacter-selective media, the distribution of cefoperazone-resistant bacteria such as extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is increasing. Here we evaluated the potential of cephamycins for use as supplements to improve modified charcoal-cefoperazone-deoxycholate agar (mCCDA) by replacing cefoperazone with the same concentrations (32 mg/L) of cefotetan (modified charcoal-cefotetan-deoxycholate agar, mCCtDA) and cefoxitin (modified charcoal-cefoxitin-deoxycholate agar, mCCxDA). In chicken carcass rinse samples, the number of mCCDA plates detecting for Campylobacter (18/70, 26%) was significantly lower than that of mCCtDA (42/70, 60%) or mCCxDA plates (40/70, 57%). The number of mCCDA plates (70/70, 100%) that were contaminated with non-Campylobacter species was significantly higher than that of mCCtDA (20/70, 29%) or mCCxDA plates (21/70, 30%). The most common competing species identified using mCCDA was ESBL-producing E. coli, while Pseudomonas species frequently appeared on mCCtDA and mCCxDA.


Assuntos
Ágar/química , Técnicas Bacteriológicas/métodos , Campylobacter/efeitos dos fármacos , Cefamicinas/farmacologia , Galinhas/microbiologia , Meios de Cultura/química , Animais , Antibacterianos/farmacologia
14.
FEMS Microbiol Lett ; 363(1): fnv215, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26564965

RESUMO

Streptomyces clavuligerus produces simultaneously cephamycin C (CephC) and clavulanic acid (CA). Adding 1,3-diaminopropane to culture medium stimulates production of beta-lactam antibiotics. However, there are no studies on the influence of this diamine on coordinated production of CephC and CA. This study indicates that 1,3-diaminopropane can dissociate CephC and CA productions. Results indicated that low diamine concentrations (below 1.25 g l(-1)) in culture medium increased CA production by 200%, but not that of CephC. Conversely, CephC production increased by 300% when 10 g l(-1) 1,3-diaminopropane was added to culture medium. Addition of just L-lysine (18.3 g l(-1)) to culture medium increased both biocompounds. On the other hand, while L-lysine plus 7.5 g l(-1) 1,3-diaminopropane increased volumetric production of CephC by 1100%, its impact on CA production was insignificant. The combined results suggest that extracellular concentration of 1,3-diaminopropane may trigger the dissociation of CephC and CA biosynthesis in S. clavuligerus.


Assuntos
Vias Biossintéticas/efeitos dos fármacos , Cefamicinas/biossíntese , Ácido Clavulânico/biossíntese , Diaminas/metabolismo , Streptomyces/efeitos dos fármacos , Streptomyces/metabolismo , Meios de Cultura/química
15.
Zhongguo Zhong Yao Za Zhi ; 40(12): 2440-4, 2015 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-26591539

RESUMO

To analyze the regularity in combined medication with Xiyanping injection (Xiyanping for short) in the real world by as- sociation rules. Totally 5 822 patients using Xiyanping injection was collected from the 18 Class III Grade I hospitals nationwide to study the combined medication information of the patient with lung infection and make the analysis by using association rules and Apriori. According to the results, major drugs combined with Xiyanping in treatment of lung infection included compound amino acid, inosine, coenzyme A, cytidine triphosphate, vitamin C. Common drugs combined with Xiyanping can be divided into 5 categories: nutrition support therapy (vitamin C, compound amino acid) , coenzymes (coenzyme A, cytidine triphosphate, inosine), expectorants and antiasthmatics (ambroxol, salbutamol, doxofylline), hormones (dexamethasone, budesonide), antibiotics (mainly cefminox). The main combined medicines mostly conformed to the regularity for drugs treating lung infection. In addition, there were two most common medical combination models: the model for Xiyanping combined a single medicine is Xiyanping + nutrition support therapy, while the model for Xiyanping combined two or more than two medicines is Xiyanping + nutrition support therapy + coenzyme. Pharmacologically, Xiyanping is mostly combined with western medicines with similar pharmacological effects to substitute or supplement the antibiotic effect in treating lung infection. However, further studies shall be conducted for the safety and rationality of the combined medication based on clinical practices, in order to provide reference for clinical medication.


Assuntos
Quimioterapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Pneumopatias/tratamento farmacológico , Adulto , Antibacterianos/administração & dosagem , Ácido Ascórbico/administração & dosagem , Cefamicinas/administração & dosagem , Feminino , Sistemas de Informação Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Antimicrob Agents Chemother ; 59(9): 5095-6, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26100709

RESUMO

Several antimicrobial agents are being investigated as alternatives to carbapenems in the treatment of infections caused by ESBL-producing Enterobacteriaceae, which may be useful in avoiding overuse of carbapenems in the context of recent global spread of carbapenem-resistant Enterobacteriaceae. The most promising candidates for invasive infections so far are ß-lactam/ß-lactamase inhibitor combinations and cephamycins.


Assuntos
Carbapenêmicos/farmacologia , Enterobacteriaceae/efeitos dos fármacos , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Cefamicinas/farmacologia , Enterobacteriaceae/enzimologia , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia
17.
J Biotechnol ; 186: 21-9, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-24975573

RESUMO

The Streptomyces clavuligerus cephamycin C gene cluster has been subcloned in a SuperCos-derived cosmid and introduced in Streptomyces flavogriseus ATCC 33331, Streptomyces coelicolor M1146 and Streptomyces albus J1074. The exconjugant strains were supplemented with an additional copy of the S. clavuligerus cephamycin regulatory activator gene, ccaRC, expressed from the constitutive Pfur promoter. Only S. flavogriseus-derived exconjugants produced a compound active against Escherichia coli ESS22-31 that was characterized by HPLC-MS as cephamycin C. The presence of an additional ccaR copy resulted in about 40-fold increase in cephamycin C production. Optimal heterologous cephamycin C production was in the order of 9% in relation to that of S. clavuligerus ATCC 27064. RT-qPCR studies indicated that ccaRC expression in S. flavogriseus::[SCos-CF] was 7% of that in S. clavuligerus and increased to 47% when supplemented with a copy of Pfur-ccaR. The effect on cephamycin biosynthesis gene expression was thus improved but not in an uniform manner for every gene. In heterologous strains, integration of the cephamycin cluster results in a ccaR-independent increased resistance to penicillin, cephalosporin and cefoxitin, what corresponds well to the strong expression of the pcbR and pbpA genes in S. flavogriseus-derived strains.


Assuntos
Antibacterianos/metabolismo , Cefamicinas/metabolismo , Família Multigênica/genética , Streptomyces/genética , Streptomyces/metabolismo , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Cefamicinas/farmacologia , Clonagem Molecular , DNA Recombinante , Técnicas de Transferência de Genes , Testes de Sensibilidade Microbiana
18.
PLoS One ; 9(7): e103253, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25068396

RESUMO

OBJECTIVES: To determine the in vitro activity of antibiotics, including arbekacin, cefminox, fosfomycin and biapenem which are all still unavailable in India, against Gram-negative clinical isolates. METHODS: We prospectively collected and tested all consecutive isolates of Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa and Acinetobacter spp. from blood, urine and sputum samples between March and November 2012. The minimum inhibition concentration (MIC) of 16 antibiotics was determined by the broth micro-dilution method. RESULTS: Overall 925 isolates were included; 211 E. coli, 207 Klebsiella spp., 153 P. aeruginosa, and 354 Acinetobacter spp. The MIC50 and MIC90 were high for cefminox, biapenem and arbekacin for all pathogens but interpretative criteria were not available. The MIC50 was categorized as susceptible for a couple of antibiotics, including piperacillin/tazobactam, carbapenems and amikacin, for E. coli, Klebsiella spp. and P. aeruginosa. However, for Acinetobacter spp., the MIC50 was categorized as susceptible only for colistin. On the other hand, fosfomycin was the only antibiotic that inhibited 90% of E. coli and Klebsiella spp. isolates, while 90% of P. aeruginosa isolates were inhibited only by colistin. Finally, 90% of Acinetobacter spp. isolates were not inhibited by any antibiotic tested. CONCLUSION: Fosfomycin and colistin might be promising antibiotics for the treatment of infections due to E. coli or Klebsiella spp. and P. aeruginosa, respectively, in India; however, clinical trials should first corroborate the in vitro findings. The activity of tigecycline should be evaluated, as this is commonly used as last-resort option for the treatment of multidrug-resistant Acinetobacter infections.


Assuntos
Cefamicinas/farmacologia , Dibecacina/análogos & derivados , Fosfomicina/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Tienamicinas/farmacologia , Acinetobacter/efeitos dos fármacos , Acinetobacter/fisiologia , Antibacterianos/farmacologia , Dibecacina/farmacologia , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Escherichia coli/fisiologia , Bactérias Gram-Negativas/fisiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Índia , Klebsiella/efeitos dos fármacos , Klebsiella/fisiologia , Testes de Sensibilidade Microbiana/métodos , Estudos Prospectivos , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia
20.
Microb Biotechnol ; 7(3): 221-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24450885

RESUMO

Streptomyces clavuligerus ATCC 27064 and S. clavuligerus ΔccaR::tsr cultures were grown in asparagine-starch medium, and samples were taken in the exponential and stationary growth phases. Transcriptomic analysis showed that the expression of 186 genes was altered in the ccaR-deleted mutant. These genes belong to the cephamycin C gene cluster, clavulanic acid gene cluster, clavams, holomycin, differentiation, carbon, nitrogen, amino acids or phosphate metabolism and energy production. All the clavulanic acid biosynthesis genes showed Mc values in the order of -4.23. The blip gene-encoding a ß-lactamase inhibitory protein was also controlled by the cephamycin C-clavulanic acid cluster regulator (Mc -2.54). The expression of the cephamycin C biosynthesis genes was greatly reduced in the mutant (Mc values up to -7.1), while the genes involved in putative ß-lactam resistance were less affected (Mc average -0.88). Genes for holomycin biosynthesis were upregulated. In addition, the lack of clavulanic acid and cephamycin production negatively affected the expression of genes for the clavulanic acid precursor arginine and of miscellaneous genes involved in nitrogen metabolism (amtB, glnB, glnA3, glnA2, glnA1). The transcriptomic results were validated by quantative reverse transcription polymerase chain reaction and luciferase assay of luxAB-coupled promoters. Transcriptomic analysis of the homologous genes of S. coelicolor validated the results obtained for S. clavuligerus primary metabolism genes.


Assuntos
Vias Biossintéticas/genética , Cefamicinas/metabolismo , Ácido Clavulânico/metabolismo , Regulação Bacteriana da Expressão Gênica , Família Multigênica , Streptomyces/metabolismo , Fatores de Transcrição/genética , Meios de Cultura/química , Deleção de Genes , Perfilação da Expressão Gênica , Genes Reporter , Luciferases/análise , Luciferases/genética , Reação em Cadeia da Polimerase em Tempo Real , Streptomyces/genética , Streptomyces/crescimento & desenvolvimento
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