RESUMO
BACKGROUND: The treatment of acne vulgaris is often challenging due to the antibiotic resistance frequently observed in Cutibacterium acnes (C.acnes), a prevalent bacterium linked to this condition. OBJECTIVE: The objective of this research was to examine the impact of curcumin photodynamic therapy (PDT) on the survival of C.acnes and activity of biofilms produced by this microorganism. METHODS: Following the Clinical and Laboratory Standards Institute (CLSI) guidelines, we assessed the drug sensitivity of 25 clinical C.acnes strains to five antibiotics (erythromycin, clindamycin, tetracycline, doxycycline, minocycline) and curcumin by implementing the broth microdilution technique. In addition, we established C.acnes biofilms in a laboratory setting and subjected them to curcumin-PDT(curcumin combined with blue light of 180 J/cm2). Afterwards, we evaluated their viability using the XTT assay and observed them using confocal laser scanning microscopy. RESULTS: The result revealed varying resistance rates among the tested antibiotics and curcumin, with erythromycin, clindamycin, tetracycline, doxycycline, minocycline, and curcumin exhibiting resistance rates of 72 %, 44 %, 36 %, 28 %, 0 %, and 100 %, respectively. In the curcumin-PDT inhibition tests against four representative antibiotic-resistant strains, it was found that the survival rate of all strains of planktonic C. acnes was reduced, and the higher the concentration of curcumin, the lower the survival rate. Furthermore, in the biofilm inhibition tests, the vitality and three-dimensional structure of the biofilms were disrupted, and the inhibitory effect became more significant with higher concentrations of curcumin. CONCLUSION: The results emphasize the possibility of using curcumin PDT as an alternative approach for the treatment of C.acnes, especially in instances of antibiotic-resistant variations and infections related to biofilms.
Assuntos
Acne Vulgar , Curcumina , Fotoquimioterapia , Humanos , Clindamicina/farmacologia , Clindamicina/uso terapêutico , Doxiciclina/farmacologia , Doxiciclina/uso terapêutico , Curcumina/farmacologia , Curcumina/uso terapêutico , Minociclina/farmacologia , Minociclina/uso terapêutico , Testes de Sensibilidade Microbiana , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Acne Vulgar/tratamento farmacológico , Antibacterianos/uso terapêutico , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Tetraciclina/farmacologia , Tetraciclina/uso terapêutico , Biofilmes , Propionibacterium acnesRESUMO
The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against Pseudomonas aeruginosa and erythromycin against Escherichia coli. Compounds 14b, 15b, 17c, 18a, 18b, 18d, 19b, 19e, 20c and 20d exhibited strong growth inhibition of methicillin-resistant Staphylococcus aureus (MRSA) and Cryptococcus neoformans, with minimum inhibitory concentrations (MIC) typically less than 0.2 µM. Four analogues, including a 5-bromo 15c and three 5-methoxyls 16d-f, also exhibited intrinsic activity towards E. coli. Antibiotic kill curve analysis of 15c identified it to be a bactericide. While only one derivative was found to (weakly) enhance the action of erythromycin against E. coli, three examples, including 15c, were found to be strong enhancers of the antibiotic action of doxycycline against P. aeruginosa. Collectively, these results highlight the promising potential of α,ω-disubstituted indole-3-acetamido polyamine conjugates as antimicrobials and antibiotic adjuvants.
Assuntos
Anti-Infecciosos , Ácidos Graxos Ômega-3 , Staphylococcus aureus Resistente à Meticilina , Antibacterianos/farmacologia , Doxiciclina , Escherichia coli , Adjuvantes Imunológicos , Adjuvantes Farmacêuticos , Eritromicina/farmacologia , Indóis/farmacologia , Poliaminas/farmacologia , Pseudomonas aeruginosaRESUMO
In this study, the cellular metabolic mechanisms regarding ammonium sulfate supplementation on erythromycin production were investigated by employing targeted metabolomics and metabolic flux analysis. The results suggested that the addition of ammonium sulfate stimulates erythromycin biosynthesis. Targeted metabolomics analysis uncovered that the addition of ammonium sulfate during the late stage of fermentation resulted in an augmented intracellular amino acid metabolism pool, guaranteeing an ample supply of precursors for organic acids and coenzyme A-related compounds. Therefore, adequate precursors facilitated cellular maintenance and erythromycin biosynthesis. Subsequently, an optimal supplementation rate of 0.02 g/L/h was determined. The results exhibited that erythromycin titer (1311.1 µg/mL) and specific production rate (0.008 mmol/gDCW/h) were 101.3% and 41.0% higher than those of the process without ammonium sulfate supplementation, respectively. Moreover, the erythromycin A component proportion increased from 83.2% to 99.5%. Metabolic flux analysis revealed increased metabolic fluxes with the supplementation of three ammonium sulfate rates.
Assuntos
Saccharopolyspora , Saccharopolyspora/metabolismo , Sulfato de Amônio , Fermentação , Eritromicina/farmacologia , Suplementos NutricionaisRESUMO
INTRODUCTION: Antimicrobial resistance (AMR) is one of the greatest threats to animal and public health. Clostridioides (prev. Clostridium) difficile is a major burden to healthcare and a relevant AMR gene reservoir. Despite the known importance of AMR in C. difficile epidemiology and treatment, antimicrobial susceptibility testing for this pathogen is still based on the determination of the minimal inhibitory concentration (MIC) by the agar dilution method, which is technically demanding and labor-intensive. In this study, the disk diffusion method was used to evaluate the susceptibility of C. difficile to erythromycin, rifampicin, and tetracycline. MATERIAL AND METHODS: A total of 155 isolates isolated between 2011 and 2022 from humans and animals in Brazil were simultaneously tested using the disk diffusion method and the epsilometer test (Etest) for these three antimicrobials on Brucella blood agar supplemented with vitamin K and hemin. RESULTS: The results suggest that disk diffusion can be an interesting routine tool to identify erythromycin- and rifampicin-resistant C. difficile isolates (≥20 mm cut-off) and wild type (WT) strains (≥28 mm). However, the disk diffusion protocol tested in this study does not seem suitable for tetracycline because of the common misclassification of resistant strains.
Assuntos
Clostridioides difficile , Humanos , Animais , Eritromicina/farmacologia , Rifampina/farmacologia , Clostridioides , Ágar , Antibacterianos/farmacologia , Tetraciclina/farmacologia , Testes de Sensibilidade Microbiana , ClostridiumRESUMO
Background: Antibiotic-resistant pathogens became a real global threat to human and animal health. This needs to concentrate the efforts to minimize and control these organisms. Efflux pumps are considered one of the important strategies used by bacteria to exclude harmful materials from the cell. Inhibition of these pumps can be an active strategy against multidrug resistance pathogens. There are two sources of efflux pump inhibitors that can be used, chemical and natural inhibitors. The chemical origin efflux pump inhibitors have many toxic side effects while the natural origin is characterized by a wide margin of safety for the host cell. Aim: In this study, the ability of some plant extracts like (propolis show rosemary, clove, capsaicin, and cumin) to potentiate the inhibitory activity of some antibiotics such as (ciprofloxacin, erythromycin, gentamycin, tetracycline, and ampicillin) against Staphylococcus aureus pathogen were tested. Methods: Efflux pump inhibitory activity of the selected plant extracts was tested using an ethidium bromide (EtBr) accumulation assay. Results: The results have shown that Propolis has a significant synergistic effect in combination with ciprofloxacin, erythromycin, and gentamycin. While it has no effect with tetracycline or ampicillin. Also, no synergic effect was noticed in a combination of the minimum inhibitory concentration for the selected plant extracts (rosemary, clove, capsaicin, and cumin) with any of the tested antibiotics. Interestingly, according to the results of the EtBr accumulation assay, Propolis has potent inhibitory activity against the S. aureus (MRS usa300) pump system. Conclusion: This study suggests that Propolis might act as a resistance breaker that is able to restore the activity of ciprofloxacin, erythromycin, and gentamycin against S. aureus strains, in case of the efflux-mediated antimicrobial resistance mechanisms.
Assuntos
Própole , Infecções Estafilocócicas , Animais , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Staphylococcus aureus , Extratos Vegetais/farmacologia , Capsaicina/farmacologia , Capsaicina/uso terapêutico , Própole/farmacologia , Própole/uso terapêutico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/uso terapêutico , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/veterinária , Tetraciclina/farmacologia , Tetraciclina/uso terapêutico , Ciprofloxacina/farmacologia , Ciprofloxacina/uso terapêutico , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Etídio/farmacologia , Etídio/uso terapêutico , Ampicilina/farmacologia , Ampicilina/uso terapêutico , Gentamicinas/farmacologiaRESUMO
Context: Ischemic stroke accounts for 85% of all types of stroke. Ischemic preconditioning can provide protection against cerebral ischemic injury. Erythromycin can induce ischemic preconditioning in brain tissue. Objective: The study intended to investigate the protective effects of erythromycin preconditioning on infarct volume after focal cerebral ischemia in rats and on the expression of tumor necrosis factor-alpha (TNF-α) and neuronal nitric oxide synthases (nNOS) in rat-brain tissue. Design: The research team performed an animal study. Setting: The study took place in the Department of Neurosurgery at the First Hospital of China Medical University in Shenyang, China. Animals: The animals were 60 healthy male Wistar rats, aged 6 to 8 weeks and weighing 270 to 300 g. Intervention: The research team randomly divided the rats into a control group in simple randomization and intervention groups preconditioning them according to their body weights using different concentrations of erythromycin-5, 20, 35, 50, and 65 mg/kg, with 10 rats in each group. The team induced focal cerebral ischemia and reperfusion using a modified, longa-wire embolization method. The control group, also 10 rats, received an injection intramuscularly of normal saline. Outcome Measures: The research team: (1) calculated the volume of cerebral infarction using triphenyltetrazolium chloride (TTC) staining with image analysis software and (2) investigated the effects of erythromycin preconditioning on the expression of TNF-α and nNOS mRNA and protein in the rat-brain tissue using real-time polymerase chain reaction (PCR) and Western blot. Results: Erythromycin preconditioning reduced the volume of cerebral infarction after induction of cerebral ischemia, showing a U-shaped, dose-response relationship, and the cerebral infarction volume significantly decreased in the 20-, 35-, and 50-mg/kg erythromycin preconditioning groups (P < .05). Erythromycin preconditioning at 20-, 35-, and 50-mg/kg significantly down-regulated the mRNA and protein expression of TNF-α in the rat-brain tissue (P < .05), with the 35-mg/kg erythromycin preconditioning group having the most significant downregulation. Erythromycin preconditioning at 20-, 35-, and 50-mg/kg upregulated the mRNA and protein expression of nNOS in the rat-brain tissue (P < .05), with the 35-mg/kg erythromycin preconditioning group having the most significant upregulation of the mRNA and protein of nNOS. Conclusions: Erythromycin preconditioning had a protective effect against focal cerebral ischemia in rats, and the best protective effect occurred for the 35-mg/kg preconditioning. The reason may be related to the fact that erythromycin preconditioning significantly upregulated nNOS and downregulated TNF-α in the brain tissue.
Assuntos
Isquemia Encefálica , Fator de Necrose Tumoral alfa , Animais , Masculino , Ratos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Infarto Cerebral , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Ratos Sprague-Dawley , Ratos Wistar , RNA Mensageiro , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Gram-negative bacteria are intrinsically resistant to a plethora of antibiotics that effectively inhibit the growth of Gram-positive bacteria. The intrinsic resistance of Gram-negative bacteria to classes of antibiotics, including rifamycins, aminocoumarins, macrolides, glycopeptides, and oxazolidinones, has largely been attributed to their lack of accumulation within cells due to poor permeability across the outer membrane, susceptibility to efflux pumps, or a combination of these factors. Due to the difficulty in discovering antibiotics that can bypass these barriers, finding targets and compounds that increase the activity of these ineffective antibiotics against Gram-negative bacteria has the potential to expand the antibiotic spectrum. In this study, we investigated the genetic determinants for resistance to rifampicin, novobiocin, erythromycin, vancomycin, and linezolid to determine potential targets of antibiotic-potentiating compounds. We subsequently performed a high-throughput screen of â¼50,000 diverse, synthetic compounds to uncover molecules that potentiate the activity of at least one of the five Gram-positive-targeting antibiotics. This led to the discovery of two membrane active compounds capable of potentiating linezolid and an inhibitor of lipid A biosynthesis capable of potentiating rifampicin and vancomycin. Furthermore, we characterized the ability of known inhibitors of lipid A biosynthesis to potentiate the activity of rifampicin against Gram-negative pathogens.
Assuntos
Antibacterianos , Oxazolidinonas , Antibacterianos/química , Antibacterianos/farmacologia , Eritromicina/farmacologia , Bactérias Gram-Negativas/genética , Linezolida , Lipídeo A , Novobiocina/farmacologia , Oxazolidinonas/farmacologia , Rifampina/farmacologia , Vancomicina/farmacologiaRESUMO
ABSTRACT: This study was conducted to evaluate the association between a therapeutic dose of tulathromycin for bovine respiratory disease in beef steers and the antimicrobial and multidrug resistance profiles of the gastrointestinal tract commensals Escherichia coli and Enterococcus spp. and the foodborne pathogens Salmonella enterica and Campylobacter spp. isolated from fecal samples. Individual fecal samples were collected on days 0, 14, and 28 from 70 beef steers that were housed in a single pen and had been treated or not treated with tulathromycin. Samples were cultured for bacterial isolation, and isolates were tested for antimicrobial susceptibility with the broth microdilution method to determine the MICs of clinically relevant antimicrobials used in both human and veterinary medicine. Generalized linear mixed effects models were fitted to estimate the prevalence of the bacterial species and the prevalence of resistant isolates over time and between treated and nontreated cattle and of multidrug-resistant isolates. Model-adjusted mean prevalences of E. coli, Enterococcus spp., S. enterica, and Campylobacter spp. were 99.5, 85.9, 1.5, and 17.7%, respectively. The prevalence of erythromycin-resistant Enterococcus spp. was significantly higher on day 14 (59.7%) than on day 28 (22.2%). A higher prevalence of erythromycin-resistant Enterococcus spp. was found in samples from treated (59.3%) than in samples from nontreated (27.6%) animals. Multidrug resistance (three or more antimicrobial classes) was observed in 8.4% of E. coli isolates and 62.7% of Enterococcus isolates. The administration of tulathromycin was significantly associated with an increased prevalence of erythromycin-resistant Enterococcus spp. isolates.
Assuntos
Anti-Infecciosos , Doenças dos Bovinos , Salmonella enterica , Animais , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Bovinos , Doenças dos Bovinos/microbiologia , Dissacarídeos , Farmacorresistência Bacteriana , Enterococcus , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Escherichia coli , Fezes/microbiologia , Compostos Heterocíclicos , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Allergic rhinitis (AR) and chronic rhinosinusitis (CRS) share some similar pathological mechanisms. In current study, we intend to investigate the impact of AR on CRS. In addition, we explored the efficacy of erythromycin (EM) treatment on CRS mice with or without AR (CRSwoAR, CRSwAR). Study subjects were divided into control, CRSwoAR, and CRSwAR groups. Experimental mice were divided similarly into control, CRSwoAR, and CRSwAR groups. In addition, CRS mice were treated with EM at 0.75, 7.5, or 75 mg/kg or with dexamethasone (Dex) at 1 mg/kg. In our results, allergy exacerbates inflammation that was evident in nasal histology and cytokine expression both in patients and in mice with CRS. Dex 1 mg/kg, EM 7.5 or 75 mg/kg treatments significantly inhibited serum IgE and IgG2a in CRS mice. EM-treated CRS mice had significantly elevated IL-10 levels and had a reversal of Th-1/Th-2 cytokine expression in nasal-associated lymphoid tissue. MUC5AC expressions were significantly reduced in the 7.5 or 75 mg/kg EM-treated mice compared with untreated mice. EM showed inhibitions on immunoglobulin production and mucus secretion stronger than Dex. We concluded that comorbid AR enhanced inflammation of CRS. EM and Dex treatments showed similar anti-inflammatory effects on CRS but through partly different mechanisms.
Assuntos
Antibacterianos/uso terapêutico , Eritromicina/uso terapêutico , Mucosa Nasal/metabolismo , Rinite Alérgica/complicações , Sinusite/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença Crônica , Citocinas/metabolismo , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Eritromicina/farmacologia , Feminino , Humanos , Imunoglobulina E/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Muco/metabolismo , Rinite Alérgica/tratamento farmacológico , Rinite Alérgica/metabolismo , Sinusite/tratamento farmacológico , Sinusite/metabolismo , Adulto JovemRESUMO
The bacterial pathogen Acinetobacter baumannii has emerged as an urgent threat to health care systems. The prevalence of multidrug resistance in this critical human pathogen is closely associated with difficulties in its eradication from the hospital environment and its recalcitrance to treatment during infection. The development of resistance in A. baumannii is in part due to substantial plasticity of its genome, facilitating spontaneous genomic evolution. Many studies have investigated selective pressures imposed by antibiotics on genomic evolution, but the influence of high-abundance bioactive molecules at the host-pathogen interface on mutation and rates of evolution is poorly understood. Here, we studied the roles of host fatty acids in the gain in resistance to common antibiotics. We defined the impact of the polyunsaturated fatty acids arachidonic acid and docosahexaenoic acid on the development of resistance to erythromycin in A. baumannii strain AB5075_UW using a microevolutionary approach. We employed whole-genome sequencing and various phenotypic analyses to characterize microbe-lipid-antibiotic interactions. Cells exposed to erythromycin in the presence of the fatty acids displayed significantly lower rates of development of resistance to erythromycin and, importantly, tetracycline. Subsequent analyses defined diverse means by which host fatty acids influence the mutation rates. This work has highlighted the critical need to consider the roles of host fatty acids in A. baumannii physiology and antimicrobial resistance. Collectively, we have identified a novel means to curb the development of resistance in this critical human pathogen. IMPORTANCE The global distribution of multidrug resistance in A. baumannii has necessitated seeking not only alternative therapeutic approaches but also the means to limit the development of resistance in clinical settings. Highly abundant host bioactive compounds, such as polyunsaturated fatty acids, are readily acquired by A. baumannii during infection and have been illustrated to impact the bacterium's membrane composition and antibiotic resistance. In this work, we show that in vitro supplementation with host polyunsaturated fatty acids reduces the rate at which A. baumannii gains resistance to erythromycin and tetracycline. Furthermore, we discover that the impact on resistance development is closely associated with the primary antimicrobial efflux systems of A. baumannii, which represent one of the major drivers of clinical resistance. Overall, this study emphasizes the potential of host macromolecules in novel approaches to circumvent the difficulties of multidrug resistance during A. baumannii treatment, with fatty acid supplements such as fish oil providing safe and cost-effective ways to enhance host tolerance to bacterial infections.
Assuntos
Acinetobacter baumannii/genética , Antibacterianos/farmacologia , Ácido Araquidônico/metabolismo , Ácidos Docosa-Hexaenoicos/metabolismo , Farmacorresistência Bacteriana Múltipla/genética , Eritromicina/farmacologia , Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/crescimento & desenvolvimento , Membrana Celular/química , Genoma Bacteriano/genética , Humanos , Testes de Sensibilidade Microbiana , Taxa de Mutação , Seleção Genética/genética , Tetraciclinas/farmacologia , Sequenciamento Completo do GenomaRESUMO
The objective of this study was to evaluate the clinical outcomes and safety of clindamycin combination antibiotherapy for the treatment of erythromycin-resistant, lincosamide-susceptible bone and joint infections caused by Staphylococcus spp. Between January 2010 and September 2018, 46 patients with Staphylococcus spp. erythromycin-resistant, lincosamide-susceptible bone and joint infections were treated with clindamycin combination antibiotherapy for 6 to 12â¯weeks. The type of infection was prosthetic in 20 cases (43.5%), osteosynthetic device in 15 cases (32.6%), chronic osteomyelitis in 7 cases (15.2%), and arthritis in 4 cases (8.7%). The cure rate was 67.4% by intention to treat and 84.6% per protocol, with a median follow-up of 398â¯days (range 86-843). Only 2 relapses (5.1%) were observed in patients with chronic osteomyelitis; an acquired resistance to lincosamides developed in 1 case. Clindamycin combination therapy appears to be effective for the treatment of bone and joint infection caused by erythromycin-resistant, lincosamide-susceptible Staphylococcus spp.
Assuntos
Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Clindamicina/uso terapêutico , Osteomielite/tratamento farmacológico , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Idoso , Artrite Infecciosa/microbiologia , Osso e Ossos/microbiologia , Farmacorresistência Bacteriana/fisiologia , Quimioterapia Combinada , Eritromicina/farmacologia , Feminino , Humanos , Articulações/microbiologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Osteomielite/microbiologia , Infecções Relacionadas à Prótese/microbiologia , Rifampina/uso terapêutico , Staphylococcus/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosRESUMO
BACKGROUND: The global prevalent ptxP3 strains varies from about 10% to about 50% of circulating B. pertussis population in different areas of China. METHODS: To investigate the difference of vaccination status between different genotypes in the circulating B. pertussis after 10 years of acellular pertussis vaccine (aPV) used in China. The nasopharyngeal swabs and isolates of B. pertussis from these patients were used to perform genotyping of antigen genes. We use antibiotic susceptibility test against erythromycin and sequencing methods for site 2047 of 23S rRNA to determine the resistance status. RESULTS: The ptxP1 allele with erythromycin resistant (ER) B. pertussis infection (total of 449 subjects) consisted of 84.70 to 96.70% from 2012 to 2016 in this study. Vaccinated with co-purified aPV was found in 133(133/403,33.0%), 1(1/9,11.1%) and 2(2/21,9.5%) in ptxP1/fhaB3-ER, ptxP1/fhaB2-ES and ptxP3/fhaB2-ES B. pertussis infected children each, which showed a significant difference (χ2 = 6.87, P = 0.032). CONCLUSIONS: The ptxP3-ES B. pertussis was rare while the ptxP1-ER B. pertussis was steadily increased in Xi'an, China from 2012 to 2016, where co-purified aPV was prevalent used. This pose a hypothesis that the co-purified aPV might protect against ptxP3 strains more efficient, which generated a rare chance for ptxP3 strains to be under the antibiotic pressure and further developed to be erythromycin resistance. A further cohort study and the mechanisms of the additional antigen proteins of co-purified aPV protected against B. pertussis should be consideration.
Assuntos
Bordetella pertussis/efeitos dos fármacos , Bordetella pertussis/genética , Toxina Pertussis/genética , Vacina contra Coqueluche/uso terapêutico , Coqueluche/epidemiologia , Alelos , Antibacterianos/farmacologia , Bordetella pertussis/isolamento & purificação , Pré-Escolar , China/epidemiologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Eritromicina/farmacologia , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Nasofaringe/microbiologia , Vacina contra Coqueluche/imunologia , Prevalência , RNA Ribossômico 23S/genética , Estudos Retrospectivos , Vacinação , Coqueluche/microbiologia , Coqueluche/prevenção & controleRESUMO
At present, there are still no official or semi-official recommendations for the treatment of muscle fatigue. We previously reported that acute phase protein orosomucoid (ORM) can enhance muscle endurance and exert anti-fatigue effect. In attempting to seek anti-fatigue drugs that target ORM, we found macrolide antibiotics, particularly erythromycin, were effective. Erythromycin can significantly prolong the time of mice forced-swimming and treadmill running, increase muscle fatigue index, alleviate fatigue-induced tissue damage, and elevate glycogen content, mitochondria function and ATP level in the muscle. Also, erythromycin increases ORM protein expression in a dose- and time- dependent manner both in vitro and in vivo. Further studies found that erythromycin could increase the activity of ORM promoter and the stability of ORM mRNA, which might both be responsible for the ORM up-regulation. ORM knockdown or knockout could abolish the promoting effect of erythromycin in mice forced-swimming time, muscle fatigue index and glycogen level. Furthermore, those effects were also abolished in mice with C-C motif chemokine receptor 5 (CCR5) antagonist administration or AMPKα2 deficiency. Therefore, erythromycin could enhance muscle glycogen and endurance via up-regulating the level of ORM and activating CCR5-AMPK pathway, indicating it might act as a potential drug to treat muscle fatigue.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Eritromicina/farmacologia , Fadiga Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Orosomucoide/metabolismo , Resistência Física/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica , Glicogênio/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Orosomucoide/genética , Receptores CCR5/metabolismo , Corrida , Transdução de Sinais , Natação , Fatores de TempoRESUMO
Long-term hepatocyte culture systems such as HepatoPac are well suited to evaluate the metabolic turnover of low clearance (CL) drugs because of their sustained metabolic capacity and longer-term viability. Erythromycin (ERY), a moderate, mechanism-based inhibitor of CYP3A, was evaluated as a tool in the HepatoPac model to assess contribution of CYP3A to the clearance of drug candidates. ERY inhibited CYP3A activity by 58% and 80% at 3 and 10 µM, respectively, for up to 72 hours. At 30 µM, ERY inhibited midazolam hydroxylation by >85% for the entire 144-hour duration of the incubation. Alprazolam CLint was inhibited 58% by 3 µM of ERY, 75% by 15 µM of ERY, 89% by 30 µM of ERY, and 94% by 60 µM of ERY. ERY (30 µM) did not markedly affect CLint of substrates for several other major cytochrome P450 isoforms evaluated and did not markedly inhibit uridine diphosphoglucuronosyl transferase (UGT) isoforms 1A1, 1A3, 1A4, 1A6, 1A9, 2B7, or 2B15 as assessed using recombinant UGTs. ERY only mildly increased CYP3A4 gene expression by 2.1-fold (14% of rifampicin induction) at 120 µM, indicating that at effective concentrations for inhibition of CYP3A activity (30-60 µM), arylhydrocarbon receptor, constitutive androstane receptor, and pregnane-X-receptor activation are not likely to markedly increase levels of other drug-metabolizing enzymes or transporters. ERY at concentrations up to 60 µM was not toxic for up to 6 days of incubation. Use of ERY to selectively inhibit CYP3A in high-functioning, long-term hepatocyte models such as HepatoPac can be a valuable strategy to evaluate the contribution of CYP3A metabolism to the overall clearance of slowly metabolized drug candidates. SIGNIFICANCE STATEMENT: This work describes the use of erythromycin as a selective inhibitor of CYP3A to assess the contribution of CYP3A in the metabolism of compounds using long-term hepatocyte cultures.
Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Eritromicina/farmacologia , Eliminação Hepatobiliar/efeitos dos fármacos , Adulto , Alprazolam/farmacocinética , Células Cultivadas , Técnicas de Cocultura/métodos , Indutores do Citocromo P-450 CYP3A/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Glucuronosiltransferase/metabolismo , Hepatócitos , Humanos , Masculino , Midazolam/farmacocinética , Pessoa de Meia-Idade , Cultura Primária de Células/métodos , Rifampina/farmacologia , Fatores de TempoRESUMO
BACKGROUND: The antibiotics generally used in farm animals are rapidly losing their effectiveness all over the world as bacteria develop antibiotic resistance. Like some other pathogenic bacteria multidrug-resistant strains of Salmonella enterica serovar Typhimurium (S. Typhimurium) are also frequently found in animals and humans which poses a major public health concern. New strategies are needed to block the development of resistance and to prolong the life of traditional antibiotics. Thus, this study aimed to increase the efficacy of existing antibiotics against S. Typhimurium by combining them with opportunistic phenolic compounds gallic acid (GA), epicatechin, epicatechin gallate, epigallocatechin and hamamelitannin. Fractional inhibitory concentration indexes (FICI) of phenolic compound-antibiotic combinations against S. Typhimurium were determined. Based on the FICI and clinical importance, 1 combination (GA and ceftiofur) was selected for evaluating its effects on the virulence factors of this bacterium. Viability of Rattus norvegicus (IEC-6) cell in presence of this antibacterial combination was evaluated. RESULTS: Minimum inhibitory concentrations (MICs) of GA, epigallocatechin and hamamelitannin found against different strains of S. Typhimurium were 256, (512-1024), and (512-1024) µg/mL, respectively. Synergistic antibacterial effect was obtained from the combination of erythromycin-epicatechin gallate (FICI: 0.50) against S. Typhimurium. Moreover, additive effects (FICI: 0.502-0.750) were obtained from 16 combinations against this bacterium. The time-kill assay and ultrastructural morphology showed that GA-ceftiofur combination more efficiently inhibited the growth of S. Typhimurium compared to individual antimicrobials. Biofilm viability, and swimming and swarming motilities of S. Typhimurium in presence of GA-ceftiofur combination were more competently inhibited than individual antimicrobials. Viabilities of IEC-6 cells were more significantly enhanced by GA-ceftiofur combinations than these antibacterials alone. CONCLUSIONS: This study suggests that GA-ceftiofur combination can be potential medication to treat S. Typhimurium-associated diarrhea and prevent S. Typhimurium-associated blood-stream infections (e.g.: fever) in farm animals, and ultimately its transmission from animal to human. Further in vivo study to confirm these effects and safety profiles in farm animal should be undertaken for establishing these combinations as medications.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Fenóis/farmacologia , Salmonelose Animal/microbiologia , Salmonella typhimurium/fisiologia , Animais , Animais Domésticos , Biofilmes/crescimento & desenvolvimento , Catequina/análogos & derivados , Catequina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cefalosporinas/farmacologia , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Sinergismo Farmacológico , Eritromicina/farmacologia , Ácido Gálico/farmacologia , Testes de Sensibilidade Microbiana , Ratos , Salmonelose Animal/tratamento farmacológico , Salmonella typhimurium/efeitos dos fármacos , SorogrupoRESUMO
AIMS: Antibiotic adjuvants can give a second life to the antibiotics to which bacteria are highly resistant. We evaluated the antimicrobial effects of extracts from Pithecellobium clypearia against methicillin-resistant Staphylococcus aureus (MRSA) and also the potential for synergy with several antibiotics. METHODS AND RESULTS: For this study, four extracts from P. clypearia were tested on MRSA using the broth microdilution method for activity assessment. The ethyl acetate fraction (S20b) had the strongest antibacterial activity against MRSA among the fractions tested. In all, 14 compounds such as gallic acid and luteolin in S20b were analysed by UFLC-Q-TOF-MS/MS. S20b combined with erythromycin showed synergy effects against MRSA and combined with ceftriaxone sodium and levofloxacin showed additive effects against MRSA. Electron microscopy showed that extract S20b damaged the MRSA cell wall and K+ efflux measurements indicated that extract S20b increased cell membrane permeability. Moreover, S20b suppression of PBP2a expression was assessed by Western blot. Furthermore, an in vivo study was used to investigate the therapeutic potential of S20b based on a mouse pneumonia model. CONCLUSIONS: The in vitro study results have shown that S20b not only inhibits MRSA growth directly but also reduces the resistance of MRSA to the evaluated antibacterial agents. Based on the in vivo study, it can be concluded that S20b can treat pneumonia in the mouse model. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first research to demonstrate that S20b can inhibit MRSA growth and reduce drug resistance of clinical isolates to antibiotics. S20b has the potential to be used as a therapeutic agent against MRSA and treatment for MRSA pneumonia.
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fabaceae/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Extratos Vegetais/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Animais , Ceftriaxona/farmacologia , Sinergismo Farmacológico , Eritromicina/farmacologia , Ácido Gálico/farmacologia , Levofloxacino/farmacologia , Luteolina/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Espectrometria de Massas em TandemRESUMO
Efflux pumps are integral parts of the bacterial plasma membrane that are responsible for many cases of antibiotic resistance. Modulators of drug resistance are regarded as the most suitable new antibacterial therapies. We evaluated the extracts of Sargassum polyceratium and the isolated compound pheophytin (Sp-1) for antibiotic modifying activity in strains of Staphylococcus aureus with efflux pump. The minimum inhibitory concentrations (MICs) for norfloxacin, tetracycline and erythromycin were determined by the microdilution broth method, in the absence and presence of the extract at a sub-inhibitory concentration (MIC/4). The extracts and isolated compounds showed no significant antimicrobial activity, but they changed the antibiotic activity, decreasing bacterial resistance by 2 to 4x. Using a checkerboard method, it was also possible to observe the synergistic effect (ΣFIC ≤ 0.5) between Sp-1 and the antibiotics erythromycin and norfloxacin. The results indicate that the seaweed Sargassum polyceratium and pheophytin are potential sources of an antibiotic adjuvant that modulates bacterial resistance, acting as a putative efflux pump inhibitor.
Assuntos
Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Feofitinas/farmacologia , Sargassum/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Eritromicina/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Norfloxacino/farmacologia , Feofitinas/metabolismo , Extratos Vegetais/farmacologia , Staphylococcus aureus/metabolismo , Tetraciclina/farmacologiaRESUMO
Amphotericin B (AmB) is the antifungal with the strongest fungicidal activity, but its use has several limitations, mainly associated with its toxicity. Although some lipidic and liposomal formulations that present reduced toxicity are available, their price limits their application in developing countries. Flucytosine (5FC) has shown synergistic effect with AmB for treatment of some fungal infections, such as cryptococcosis, but again, its price is a limitation for its use in many regions. In the present work, we aimed to identify new drugs that have a minor effect on Cryptococcus neoformans, reducing its growth in the presence of subinhibitory concentrations of AmB. In the initial screening, we found fourteen drugs that had this pattern. Later, checkerboard assays of selected compounds, such as erythromycin, riluzole, nortriptyline, chenodiol, nisoldipine, promazine, chlorcyclizine, cloperastine, and glimepiride, were performed and all of them confirmed for their synergistic effect (fractional inhibitory concentration index [FICI] < 0.5). Additionally, toxicity of these drugs in combination with AmB was tested in mammalian cells and in zebrafish embryos. Harmless compounds, such as the antibiotic erythromycin, were found to have synergic activity with AmB, not only against C. neoformans but also against some Candida spp., in particular against Candida albicans In parallel, we identified drugs that had antifungal activity against C. neoformans and found 43 drugs that completely inhibited the growth of this fungus, such as ciclopirox and auranofin. Our results expand our knowledge about antifungal compounds and open new perspectives in the treatment of invasive mycosis based on repurposing off-patent drugs.
Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Cryptococcus neoformans/efeitos dos fármacos , Reposicionamento de Medicamentos , Animais , Auranofina/farmacologia , Candidíase/tratamento farmacológico , Linhagem Celular , Ciclopirox/farmacologia , Criptococose/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos/métodos , Sinergismo Farmacológico , Eritromicina/farmacologia , Flucitosina/farmacologia , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia , Células RAW 264.7 , Peixe-Zebra/embriologiaRESUMO
Flavobacterium psychrophilum is responsible for significant economic losses in rainbow trout aquaculture. Antimicrobial treatment remains the primary means of control; however, there are limited choices available for use. The objectives of the study were therefore to determine the minimum inhibitory concentrations for erythromycin and florfenicol in selected F. psychrophilum isolates and to evaluate their clinical treatment efficacy in experimentally infected rainbow trout. All isolates tested had moderate susceptibility to florfenicol and erythromycin except one isolate, which had low susceptibility to erythromycin. Two isolates (one with moderate and one with low susceptibility to erythromycin) were used in an experimental infection trial. Rainbow trout juveniles were injected intraperitoneally with 108 cfu/fish and after mortality had begun, fish were given erythromycin- and florfenicol-medicated feed at a rate of 75 mg kg- 1 day- 1 and 10 mg kg- 1 day- 1 fish body weight, respectively, for 10 consecutive days. The splenic F. psychrophilum load was determined using an rpoC quantitative PCR throughout the 30-day trial. Relative to antibiotic-free controls, erythromycin treatment significantly (p < 0.05) reduced mortality of rainbow trout juveniles infected with FPG101, even when treatment was initiated after clinical signs developed.
Assuntos
Antibacterianos/farmacologia , Eritromicina/farmacologia , Doenças dos Peixes/tratamento farmacológico , Infecções por Flavobacteriaceae/veterinária , Animais , Aquicultura , Farmacorresistência Bacteriana , Doenças dos Peixes/microbiologia , Doenças dos Peixes/mortalidade , Infecções por Flavobacteriaceae/tratamento farmacológico , Infecções por Flavobacteriaceae/microbiologia , Infecções por Flavobacteriaceae/mortalidade , Flavobacterium , Testes de Sensibilidade Microbiana/veterinária , Oncorhynchus mykiss , Baço/microbiologia , Tianfenicol/análogos & derivados , Tianfenicol/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: The prokinetic action of erythromycin is clinically useful under conditions associated with gastrointestinal hypomotility. Although erythromycin is known to affect the electrogastrogram, no studies have examined the effects that erythromycin has on gastric slow wave magnetic fields. METHODS: In this study, gastric slow wave activity was assessed simultaneously using noninvasive magnetogastrogram (MGG), electrogastrogram, and mucosal electromyogram recordings. Recordings were obtained for 30 min prior to and 60 min after intravenous administration of erythromycin at dosages of 3 and 6 mg/kg. RESULTS: MGG recordings showed significant changes in the percentage power distribution of gastric signal after infusion of both 3 and 6 mg/kg erythromycin at t = 1-5 min that persisted for t = 30-40 min after infusion. These changes agree with the changes observed in the electromyogram. We did not observe any statistically significant difference in MGG amplitude before or after injection of either 3 or 6 mg/kg erythromycin. Both 3 and 6 mg/kg erythromycin infusion showed retrograde propagation with a statistically significant decrease in slow wave propagation velocity 11-20 min after infusion. Propagation velocity started returning toward baseline values after approximately 21-30 min for the 3 mg/kg dosage and after 31-40 min for a dosage of 6 mg/kg. CONCLUSION: Our results showed that the magnetic signatures were sensitive to disruptions in normal slow wave activity induced by pharmacological and prokinetic agents such as erythromycin. SIGNIFICANCE: This study shows that repeatable noninvasive bio-electro-magnetic techniques can objectively characterize gastric dysrhythmias and may quantify treatment efficacy in patients with functional gastric disorders.