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1.
BMC Microbiol ; 22(1): 152, 2022 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681117

RESUMO

BACKGROUND: Ribosome stalling on ermBL at the tenth codon (Asp) and mRNA stabilization are believed to be mechanisms by which erythromycin (Ery) induces ermB expression. Expression of ermB is also induced by 16-membered ring macrolides (tylosin, josamycin and spiramycin), but the mechanism underlying this induction is unknown. METHODS: We introduced premature termination codons, alanine-scanning mutagenesis and amino acid mutations in ermBL and ermBL2. RESULTS: In this paper, we demonstrated that 16-membered ring macrolides can induce ermB expression but not ermC expression. The truncated mutants of the ermB-coding sequence indicate that the regulatory regions of ermB whose expression is induced by Ery and 16-membered ring macrolides are different. We proved that translation of the N-terminal region of ermBL is key for the induction of ermB expression by Ery, spiramycin (Spi) and tylosin (Tyl). We also demonstrated that ermBL2 is critical for the induction of ermB expression by erythromycin but not by 16-membered ring macrolides. CONCLUSIONS: The translation of ermBL and the RNA sequence of the C-terminus of ermBL are critical for the induction of ermB expression by Spi and Tyl.


Assuntos
Eritromicina , Espiramicina , Antibacterianos/farmacologia , Eritromicina/farmacologia , Macrolídeos/farmacologia , Espiramicina/farmacologia , Tilosina
2.
World J Microbiol Biotechnol ; 38(8): 132, 2022 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-35689134

RESUMO

This study was aimed at the isolation and identification of Arcobacter spp. and Campylobacter spp. from fresh vegetables sold at district markets in the Kayseri province, and at the determination of the antibacterial susceptibility of the recovered isolates. For this purpose, a total of 175 vegetable samples, including 35 spinach, 35 lettuce, 35 parsley, 35 arugula, and 35 radish samples, were collected. While the pre-enrichment and membrane filtration techniques were used for the isolation of Arcobacter spp., the pre-enrichment and direct inoculation methods were used for the isolation of Campylobacter spp. The isolates were identified by means of phenotypic tests and the polymerase chain reaction (PCR), using genus- and species-specific primers. In addition, the susceptibilities of the isolates to amoxicillin-clavulanic acid, enrofloxacin, erythromycin, gentamicin, neomycin, streptomycin, and tetracycline were determined by the disk diffusion method. Out of the 175 vegetable samples tested, 93 (53.14%) were found to be positive for Arcobacter spp., and 119 Arcobacter spp. isolates were recovered from these 93 positive samples. All of the samples examined were found to be negative for Campylobacter spp. One hundred one (86%) and 14 (10%) of the 119 Arcobacter isolates obtained were identified as A. butzleri and A. cryaerophilus, respectively, but four isolates could not be identified at the species level by mPCR. Mixed contamination with more than one species and/or genotypes of Arcobacter was detected in 24 of the positive samples. While all of the Arcobacter isolates were susceptible to erythromycin, gentamicin, streptomycin, and tetracycline, 2 (1.68%), 2 (1.68%), and 5 (4.20%) isolates were resistant to amoxicillin/clavulanic acid, enrofloxacin, and neomycin, respectively. Consequently, the determination of a high prevalence of arcobacters and mixed contamination with more than one species and/or genotypes of arcobacters in vegetables often consumed raw by humans demonstrated that the consumption of raw vegetables may be a risk to the public health.


Assuntos
Arcobacter , Campylobacter , Antibacterianos/farmacologia , Arcobacter/genética , Campylobacter/genética , Enrofloxacina , Eritromicina/farmacologia , Microbiologia de Alimentos , Gentamicinas , Humanos , Neomicina , Prevalência , Estreptomicina , Tetraciclinas , Verduras
3.
Crit Care ; 26(1): 151, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610649

RESUMO

BACKGROUND: Immunomodulatory therapies that improve the outcome of sepsis are not available. We sought to determine whether treatment of critically ill patients with sepsis with low-dose erythromycin-a macrolide antibiotic with broad immunomodulatory effects-decreased mortality and ameliorated underlying disease pathophysiology. METHODS: We conducted a target trial emulation, comparing patients with sepsis admitted to two intensive care units (ICU) in the Netherlands for at least 72 h, who were either exposed or not exposed during this period to treatment with low-dose erythromycin (up to 600 mg per day, administered as a prokinetic agent) but no other macrolides. We used two common propensity score methods (matching and inverse probability of treatment weighting) to deal with confounding by indication and subsequently used Cox regression models to estimate the treatment effect on the primary outcome of mortality rate up to day 90. Secondary clinical outcomes included change in SOFA, duration of mechanical ventilation and the incidence of ICU-acquired infections. We used linear mixed models to assess differences in 15 host response biomarkers reflective of key pathophysiological processes from admission to day 4. RESULTS: In total, 235 patients started low-dose erythromycin treatment, 470 patients served as controls. Treatment started at a median of 38 [IQR 25-52] hours after ICU admission for a median of 5 [IQR 3-8] total doses in the first course. Matching and weighting resulted in populations well balanced for proposed confounders. We found no differences between patients treated with low-dose erythromycin and control subjects in mortality rate up to day 90: matching HR 0.89 (95% CI 0.64-1.24), weighting HR 0.95 (95% CI 0.66-1.36). There were no differences in secondary clinical outcomes. The change in host response biomarker levels from admission to day 4 was similar between erythromycin-treated and control subjects. CONCLUSION: In this target trial emulation in critically ill patients with sepsis, we could not demonstrate an effect of treatment with low-dose erythromycin on mortality, secondary clinical outcomes or host response biomarkers.


Assuntos
Estado Terminal , Sepse , Biomarcadores , Ensaios Clínicos como Assunto , Estado Terminal/terapia , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Humanos , Unidades de Terapia Intensiva , Sepse/tratamento farmacológico
4.
Transl Vis Sci Technol ; 11(5): 26, 2022 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-35612831

RESUMO

Purpose: Pseudomonas aeruginosa is a leading cause of corneal infections. Recently, we discovered an antimicrobial drug combination, polymyxin B/trimethoprim (PT) + rifampin, that displayed impressive efficacy toward P. aeruginosa in both in vitro and in vivo studies. As such, this combination was further evaluated as a potential keratitis therapeutic through testing the combination's efficacy against a diverse set of P. aeruginosa clinical isolates. Methods: Minimum inhibitory concentrations (MICs) of moxifloxacin, levofloxacin, erythromycin, tobramycin, PT, polymyxin B (alone), trimethoprim (alone), and rifampin were determined for 154 ocular clinical P. aeruginosa isolates, 90% of which were derived from corneal scrapings. Additionally, the efficacy of PT + rifampin was evaluated utilizing fractional inhibitory concentration (FIC) testing. Results: While 100% of isolates were resistant to erythromycin (average MIC 224 ± 110 µg·mL-1) and trimethoprim (alone) (206 ± 67.3 µg·mL-1), antibiotic resistance was generally found to be low: moxifloxacin (2% of isolates resistant; average MIC 1.08 ± 1.61 µg·mL-1), levofloxacin (3.9%; 1.02 ± 2.96 µg·mL-1), tobramycin (1%; 0.319 ± 1.31 µg·mL-1), polymyxin B (0%; 0.539 ± 0.206 µg·mL-1), PT (0%; 0.416 ± 0.135 µg·mL-1), and rifampin (0%; 23.4 ± 6.86 µg·mL-1). Additionally, FIC testing revealed that PT + rifampin eradicated 100% of isolates demonstrating additive or synergistic activity in 95% of isolates (average FIC index 0.701 ± 0.132). Conclusions: The drug combination of PT + rifampin was effective against a large panel of clinically relevant P. aeruginosa strains and, as such, may represent a promising therapeutic for P. aeruginosa keratitis. Translational Relevance: This work furthers the preclinical development of a novel antibiotic combination for the treatment of corneal infections (bacterial keratitis).


Assuntos
Ceratite , Infecções por Pseudomonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bacitracina/farmacologia , Bacitracina/uso terapêutico , Combinação de Medicamentos , Eritromicina/farmacologia , Eritromicina/uso terapêutico , Framicetina/farmacologia , Framicetina/uso terapêutico , Humanos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Levofloxacino/farmacologia , Levofloxacino/uso terapêutico , Moxifloxacina/farmacologia , Moxifloxacina/uso terapêutico , Polimixina B/farmacologia , Polimixina B/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Rifampina/farmacologia , Rifampina/uso terapêutico , Tobramicina/farmacologia , Tobramicina/uso terapêutico , Trimetoprima/farmacologia , Trimetoprima/uso terapêutico
5.
Appl Environ Microbiol ; 88(10): e0041022, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35477272

RESUMO

Antibiotic resistance is a serious medical issue driven by antibiotic misuse. Bifidobacteria may serve as a reservoir for antibiotic resistance genes (ARGs) that have the potential risk of transfer to pathogens. The erythromycin resistance gene erm(X) is an ARG with high abundance in bifidobacteria, especially in Bifidobacterium longum species. However, the characteristics of the spread and integration of the gene erm(X) into the bifidobacteria genome are poorly understood. In this study, 10 tetW-positive bifidobacterial strains and 1 erm(X)-positive bifidobacterial strain were used to investigate the transfer of ARGs. Conjugation assays found that the erm(X) gene could transfer to five other bifidobacterial strains. Dimethyl sulfoxide (DMSO) and vorinostat significantly promoted the transfer of the erm(X) from strain Bifidobacterium catenulatum subsp. kashiwanohense DSM 21854 to Bifidobacterium longum subsp. suis DSM 20211. Whole-genome sequencing and comparative genomic analysis revealed that the erm(X) gene was located on the genomic island BKGI1 and that BKGI1 was conjugally mobile and transferable. To our knowledge, this is the first report that a genomic island-mediated gene erm(X) transfer in bifidobacteria. Additionally, BKGI1 is very unstable in B. catenulatum subsp. kashiwanohense DSM 21854 and transconjugant D2TC and is highly excisable and has an intermediate circular formation. In silico analysis showed that the BKGI1 homologs were also present in other bifidobacterial strains and were especially abundant in B. longum strains. Thus, our results confirmed that genomic island BKGI1 was one of the vehicles for erm(X) spread. These findings suggest that genomic islands play an important role in the dissemination of the gene erm(X) among Bifidobacterium species. IMPORTANCE Bifidobacteria are a very important group of gut microbiota, and the presence of these bacteria has many beneficial effects for the host. Thus, bifidobacteria have attracted growing interest owing to their potential probiotic properties. Bifidobacteria have been widely exploited by the food industry as probiotic microorganisms, and some species have a long history of safe use in food and feed production. However, the presence of antibiotic resistance raises the risk of its application. In this study, we analyzed the transfer of the erythromycin resistance gene erm(X) and revealed that the molecular mechanism behind the spread of the gene erm(X) was mediated by genomic island BKGI1. To the best of our knowledge this is the first report to describe the transfer of the gene erm(X) via genomic islands among bifidobacteria. This may be an important way to disseminate the gene erm(X) among bifidobacteria.


Assuntos
Eritromicina , Ilhas Genômicas , Antibacterianos/farmacologia , Bifidobacterium/genética , Eritromicina/farmacologia
6.
Clin Lab ; 68(4)2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35443581

RESUMO

BACKGROUND: The goal of the study was to analyze the clinical characteristics of Legionella cases caused by Legionella micdadei and explore the diagnosis and treatment. METHODS: The pathogen was identified by routine isolation and culture, biochemical identification, serum agglutination test, mass spectrometry identification, and routine PCR. Combined with the related literature review, the clinical diagnosis and treatment of Legionella micdadei were analyzed. RESULTS: The patient suffered from pulmonary infection caused by Legionella micdadei. After treatment with moxi-floxacin for 2 weeks, the body temperature dropped and the shadow of the lung was completely absorbed after 2 months. Combined with literature analysis, 8 cases of Legionella micetidis, including 7 males and 1 female, aged from 27 to 57 years old, 6 cases with basic diseases, which were treated with azithromycin, erythromycin or levofloxacin, and all of them achieved good therapeutic effect. CONCLUSIONS: The detection of Legionella should be strengthened in patients with pneumonia whose symptoms have no obvious improvement after antibiotic treatment. Azithromycin, erythromycin or levofloxacin are effective in the treatment of Legionella spp.


Assuntos
Legionella , Legionelose , Pneumonia , Adulto , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Eritromicina/farmacologia , Feminino , Humanos , Legionellaceae , Legionelose/complicações , Legionelose/diagnóstico , Legionelose/tratamento farmacológico , Levofloxacino/farmacologia , Levofloxacino/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico
7.
Antimicrob Agents Chemother ; 66(4): e0224621, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35293783

RESUMO

While the use of long-term macrolide therapy to prevent exacerbations in chronic respiratory diseases is widespread, its impact on the oropharyngeal microbiota and macrolide resistance, and the potential for onward transmission of resistance to close contacts are poorly understood. We determined the effects of long-term exposure to azithromycin or erythromycin on phenotypic and genotypic macrolide resistance within the oropharyngeal microbiome of healthy adults and their close contacts in a randomized, single-blinded, parallel-group trial of 4 weeks of twice-daily oral 400 mg erythromycin ethylsuccinate or twice-daily oral 125 mg azithromycin. Using oropharyngeal swabs collected from 20 index healthy adults and 20 paired close contacts, the oropharyngeal microbial composition and macrolide resistance in streptococci were assessed by 16S rRNA sequencing and antibiotic susceptibility testing of oropharyngeal cultures, respectively, at baseline and weeks 4 and 8 (washout). Targeted quantitative PCR of antibiotic resistance genes was performed to evaluate paired changes in resistance gene levels in index patients and close contacts and to relate the potential transmission of antibiotic resistance. Neither azithromycin nor erythromycin altered oropharyngeal microbiota characteristics significantly. Proportional macrolide resistance in oropharyngeal streptococci increased with both erythromycin and azithromycin, remaining above baseline levels for the azithromycin group at washout. Levels of resistance genes increased significantly with azithromycin[erm(B) and mef] and erythromycin (mef), returning to baseline levels at washout only for the erythromycin group. We found no evidence of onward transmission of resistance to close contacts, as indicated by the lack of concomitant changes in resistance gene levels detected in close contacts. (This study has been registered with the Australian and New Zealand Clinical Trials Registry under identifier ACTRN12617000278336.).


Assuntos
Antibacterianos , Microbiota , Adulto , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Austrália , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Farmacorresistência Bacteriana/genética , Eritromicina/farmacologia , Humanos , Macrolídeos/farmacologia , RNA Ribossômico 16S/genética , Streptococcus
8.
J Med Microbiol ; 71(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35175912

RESUMO

Introduction. Acquired resistance against the antibiotics that are active against Ureaplasma species has been described.Hypothesis/Gap Statement. Diagnostics combined with antimicrobial sensitivity testing are required for therapeutic guidance.Aim. To report the prevalence of antimicrobial resistance among Cuban Ureaplasma isolates and the related molecular mechanisms of resistance.Methodology. Traditional broth microdilution assays were used for antimicrobial sensitivity testing in 262 clinical Ureaplasma species isolates from Cuban patients between 2013 and 2018, and a subset of samples were investigated in parallel with the commercial MYCO WELL D-ONE rapid culture diagnostic assay. The underlying molecular mechanisms for resistance were determined by PCR and sequencing for all resistant isolates.Results. Among the tested isolates, the tetracycline and erythromycin resistance rates were 1.9 and 1.5%, respectively, while fluoroquinolone resistance was not found. The tet(M) gene was found in all tetracycline-resistant isolates, but also in two tetracycline-susceptible Ureaplasma clinical isolates. We were unable to determine the underlying mechanism of erythromycin resistance. The MYCO WELL D-ONE kit overestimated tetracycline and erythromycin resistance in Ureaplasma spp. isolates.Conclusions. Although low levels of antibiotic resistance were detected in Cuban patients over a 5-year period, continued surveillance of the antibiotic susceptibility of Ureaplasma is necessary to monitor possible changes in resistance patterns.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Infecções por Ureaplasma , Ureaplasma/efeitos dos fármacos , Cuba , Eritromicina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Tetraciclina/farmacologia , Ureaplasma/genética , Infecções por Ureaplasma/epidemiologia , Infecções por Ureaplasma/microbiologia
9.
Microbiol Spectr ; 10(1): e0132221, 2022 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-35019676

RESUMO

Clostridioides difficile, which causes life-threatening diarrheal disease, presents an urgent threat to health care systems. In this study, we present a retrospective genomic and epidemiological analysis of C. difficile in a large teaching hospital. First, we collected 894 nonduplicate fecal samples from patients during a whole year to elucidate the C. difficile molecular epidemiology. We then presented a detailed description of the population structure of C. difficile based on 270 isolates separated between 2015 and 2020 and clarified the genetic and phenotypic features by MIC and whole-genome sequencing. We observed a high carriage rate (19.4%, 173/894) of C. difficile among patients in this hospital. The population structure of C. difficile was diverse with a total of 36 distinct STs assigned. In total, 64.8% (175/270) of the isolates were toxigenic, including four CDT-positive (C. difficile transferase) isolates, and 50.4% (135/268) of the isolates were multidrug-resistant. Statistically, the rates of resistance to erythromycin, moxifloxacin, and rifaximin were higher for nontoxigenic isolates. Although no vancomycin-resistant isolates were detected, the MIC for vancomycin was higher for toxigenic isolates (P < 0.01). The in-hospital transmission was observed, with 43.8% (110/251) of isolates being genetically linked to a prior case. However, no strong correlation was detected between the genetic linkage and epidemiological linkage. Asymptomatic colonized patients play the same role in nosocomial transmission as infected patients, raising the issue of routine screening of C. difficile on admission. This work provides an in-depth description of C. difficile in a hospital setting and paves the way for better surveillance and effective prevention of related diseases in China. IMPORTANCE Clostridioides difficile infections (CDI) are the leading cause of healthcare-associated diarrhea and are known to be resistant to multiple antibiotics. In the past decade, C. difficile has emerged rapidly and has spread globally, causing great concern among American and European countries. However, research on CDI remains limited in China. Here, we characterized the comprehensive spectrum of C. difficile by whole-genome sequencing (WGS) in a Chinese hospital, showing a high detection rate among patients, diverse genome characteristics, a high level of antibiotic resistance, and an unknown nosocomial transmission risk of C. difficile. During the study period, two C. difficile transferase (CDT)-positive isolates belonging to a new multilocus sequence type (ST820) were detected, which have caused serious clinical symptoms. This work describes C. difficile integrally and provides new insight into C. difficile surveillance based on WGS in China.


Assuntos
Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Clostridioides difficile/genética , Infecções por Clostridium/microbiologia , Infecção Hospitalar/microbiologia , Farmacorresistência Bacteriana , Adolescente , Adulto , Idoso , Proteínas de Bactérias/genética , Criança , Pré-Escolar , China/epidemiologia , Clostridioides difficile/classificação , Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/epidemiologia , Infecções por Clostridium/transmissão , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/epidemiologia , Infecção Hospitalar/transmissão , Eritromicina/farmacologia , Feminino , Genoma Bacteriano , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Moxifloxacina/farmacologia , Filogenia , Estudos Retrospectivos , Rifaximina/farmacologia , Vancomicina/farmacologia , Sequenciamento Completo do Genoma , Adulto Jovem
10.
Microb Genom ; 8(1)2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35084301

RESUMO

Macrolides are broad-spectrum antibiotics used to treat a range of infections. Resistance to macrolides is often conferred by mobile resistance genes encoding Erm methyltransferases or Mph phosphotransferases. New erm and mph genes keep being discovered in clinical settings but their origins remain unknown, as is the type of macrolide resistance genes that will appear in the future. In this study, we used optimized hidden Markov models to characterize the macrolide resistome. Over 16 terabases of genomic and metagenomic data, representing a large taxonomic diversity (11 030 species) and diverse environments (1944 metagenomic samples), were searched for the presence of erm and mph genes. From this data, we predicted 28 340 macrolide resistance genes encoding 2892 unique protein sequences, which were clustered into 663 gene families (<70 % amino acid identity), of which 619 (94 %) were previously uncharacterized. This included six new resistance gene families, which were located on mobile genetic elements in pathogens. The function of ten predicted new resistance genes were experimentally validated in Escherichia coli using a growth assay. Among the ten tested genes, seven conferred increased resistance to erythromycin, with five genes additionally conferring increased resistance to azithromycin, showing that our models can be used to predict new functional resistance genes. Our analysis also showed that macrolide resistance genes have diverse origins and have transferred horizontally over large phylogenetic distances into human pathogens. This study expands the known macrolide resistome more than ten-fold, provides insights into its evolution, and demonstrates how computational screening can identify new resistance genes before they become a significant clinical problem.


Assuntos
Bactérias/crescimento & desenvolvimento , Biologia Computacional/métodos , Farmacorresistência Bacteriana , Macrolídeos/farmacologia , Metiltransferases/genética , Fosfotransferases/genética , Azitromicina/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Proteínas de Bactérias/genética , Eritromicina/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/crescimento & desenvolvimento , Evolução Molecular , Cadeias de Markov , Metagenômica , Testes de Sensibilidade Microbiana , Família Multigênica , Filogenia
11.
J Biol Chem ; 298(2): 101571, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35007529

RESUMO

Erythromycin resistance methyltransferases (Erms) confer resistance to macrolide, lincosamide, and streptogramin antibiotics in Gram-positive bacteria and mycobacteria. Although structural information for ErmAM, ErmC, and ErmE exists from Gram-positive bacteria, little is known about the Erms in mycobacteria, as there are limited biochemical data and no structures available. Here, we present crystal structures of Erm38 from Mycobacterium smegmatis in apoprotein and cofactor-bound forms. Based on structural analysis and mutagenesis, we identified several catalytically critical, positively charged residues at a putative RNA-binding site. We found that mutation of any of these sites is sufficient to abolish methylation activity, whereas the corresponding RNA-binding affinity of Erm38 remains unchanged. The methylation reaction thus appears to require a precise ensemble of amino acids to accurately position the RNA substrate, such that the target nucleotide can be methylated. In addition, we computationally constructed a model of Erm38 in complex with a 32-mer RNA substrate. This model shows the RNA substrate stably bound to Erm38 by a patch of positively charged residues. Furthermore, a π-π stacking interaction between a key aromatic residue of Erm38 and a target adenine of the RNA substrate forms a critical interaction needed for methylation. Taken together, these data provide valuable insights into Erm-RNA interactions, which will aid subsequent structure-based drug design efforts.


Assuntos
Proteínas de Bactérias , Eritromicina , Metiltransferases , Mycobacterium smegmatis , Antibacterianos , Proteínas de Bactérias/química , Sítios de Ligação , Resistência Microbiana a Medicamentos , Eritromicina/farmacologia , Metiltransferases/química , Metiltransferases/metabolismo , Mycobacterium smegmatis/enzimologia , RNA/química , RNA/metabolismo
12.
Environ Pollut ; 294: 118615, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34863891

RESUMO

Environmental obesogens contributed significantly to the obesity prevalence. Recently, antibiotics joined the list of environmental obesogens, while the underlying mechanisms remained to be explored. In the present study, effects of erythromycin (ERY), one widely used macrolide antibiotic, were measured on C. elegans to investigate the obesogenic mechanism. Results showed that ERY at 0.1 µg/L significantly increased the fat content by 17.4% more than the control and also stimulated triacylglycerol (TAG) levels by 25.7% more than the control. Regarding the obesogenic mechanisms, ERY provoked over-eating by stimulation on the pharyngeal pumping and reduction on the satiety quiescence percentage and duration. Such effects were resulted from stimulation on the neurotransmitters including serotonin (5-HT), dopamine (DA) and acetylcholine (ACh). The nervous responses involved the up-regulation of Gsα (e.g., ser-7, gsa-1, acy-1 and kin-2) signaling pathway and the down-regulation of TGFß (daf-7) but not via cGMP-dependent regulations (e.g., egl-4). Moreover, ERY stimulated the activities of fatty acid synthase (FAS) and glycerol-3-phosphateacyl transferases (GPAT) that catalyze lipogenesis, while ERY inhibited those of acyl-CoA synthetase (ACS), carnitine palmitoyl transferase (CPT) and acyl-CoA oxidase (ACO) that catalyze lipolysis. The unbalance between lipogenesis and lipolysis resulted in the fat accumulation which was consistent with up-regulation on mgl-1 and mgl-3 which are the down-steam of TGFß regulation. Such consistence supported the close connection between nervous regulation and lipid metabolism. In addition, ERY also disturbed insulin which connects lipid with glucose in metabolism.


Assuntos
Caenorhabditis elegans/efeitos dos fármacos , Eritromicina/farmacologia , Metabolismo dos Lipídeos , Animais , Proteínas de Caenorhabditis elegans/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipólise , Obesidade
13.
J Biomed Mater Res B Appl Biomater ; 110(2): 412-421, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34302429

RESUMO

Designing hydrogels for controlled drug delivery remains a big challenge. We developed a calcium polyphosphate hydrogel (CPP) as matrix for delivery of vancomycin (VCM) and erythromycin (EM) by unique ionic binding and physical wrapping. In this continuing study, we investigated if gel discs prepared by mechanical compaction (at 3000 psi pressure, C-discs) is superior to that of discs prepared by regular manual compaction (M-discs) for the release of VCM and EM (10 wt.%). Data demonstrated a significant reduction of burst release of VCM and EM in C-discs (1.8% and 5%, respectively) as compared to that from M-discs within 72 hr (55% and 60%, respectively, p < 0.05). In addition, C-discs significantly extended the VCM release (1500 hr) and EM (800 hr) as compared to M-discs (160 and 96 hr, respectively, p < 0.05). The VCM released from C-discs retained its bactericidal activity much longer (1500 hr) than that from M-discs (700 hr, p < 0.05). Raman Spectroscopy indicated an ionic bond of both VCM and EM with fully hydrated polyphosphate chains of CPP hydrogel matrix for both M-discs and C-discs. Micro CT showed that C-discs had much denser microstructures and less number/depth of microcracks as a result of high pressure. We propose that CPP hydrogel represents an excellent tool for the controllable and sustained delivery of VCM and EM. Extensive experiments are currently underway to evaluate the potential impacts of the modification of compaction techniques, other antibiotics, gel concentrations on the drug release, degradation behavior and infection control both in vitro and in vivo.


Assuntos
Eritromicina , Vancomicina , Antibacterianos/química , Antibacterianos/farmacologia , Cálcio , Eritromicina/farmacologia , Hidrogéis/química , Hidrogéis/farmacologia , Polifosfatos , Vancomicina/química , Vancomicina/farmacologia
14.
J Hazard Mater ; 422: 126858, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34419845

RESUMO

Toxicological effects of nanoplastics have been demonstrated in a variety of organisms, yet their impacts on bacteria, especially on the antibiotic resistance evolution remain under explored. Herein, we report individual and combined effects of nano-polystyrene (nano-PS) and erythromycin (ERY) on growth and resistance mutations of Escherichia coli. The toxicity of nano-PS was dependent on size and functional modifications, with 30 nm and amino-modified PS (PS-NH2, 200 nm) showing the greatest toxicity. Adsorption of nano-PS onto bacterial surface and the subsequent increase of intracellular ROS or the probable mechanical damage were considered as the primary toxic mechanisms. Furthermore, nano-PS increased the bacterial resistance mutations, which was due to the oxidative damage to DNA and the SOS response. In addition, PS-NH2 presented synergistic effects with ERY while non-modified PS had no impact, although both of them showed adsorption capacity to ERY. This was likely because the positively charged PS-NH2 acted as a carrier of ERY and enhanced the interactions between ERY and the bacteria. Our findings raised the concerns about the risk of nanoplastics in accelerating the bacterial resistance evolution, and highlighted the necessity of including combined effects of nanoplastics and co-contaminants in risk assessment.


Assuntos
Nanopartículas , Poliestirenos , Adsorção , Eritromicina/farmacologia , Escherichia coli/genética , Mutação , Nanopartículas/toxicidade
15.
PLoS One ; 16(12): e0261435, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34910778

RESUMO

Diphtheria is caused by a toxigenic bacterium Corynebacterium diphtheria which is being an emerging pathogen in India. Since diphtheria morbidity and mortality continues to be high in the country, the present study aimed to study the molecular epidemiology of C. diphtheriae strains from India. A total of 441 diphtheria suspected specimens collected as part of the surveillance programme between 2015 and 2020 were studied. All the isolates were confirmed as C. diphtheriae with standard biochemical tests, ELEK's test, and real-time PCR. Antimicrobial susceptibility testing for the subset of isolates showed intermediate susceptibility to penicillin and complete susceptible to erythromycin and cefotaxime. Isolates were characterized using multi locus sequence typing method. MLST analysis for the 216 C. diphtheriae isolates revealed major diversity among the sequence types. A total of 34 STs were assigned with majority of the isolates belonged to ST466 (30%). The second most common ST identified was ST405 that was present in 14% of the isolates. The international clone ST50 was also seen. The identified STs were grouped into 8 different clonal complexes (CC). The majority belongs to CC5 followed by CC466, CC574 and CC209, however a single non-toxigenic strain belongs to CC42. This epidemiological analysis revealed the emergence of novel STs and the clones with better dissemination properties. This study has also provided information on the circulating strains of C. diphtheriae among the different regions of India. The molecular data generated through surveillance system can be utilized for further actions in concern.


Assuntos
Antibacterianos/farmacologia , Corynebacterium diphtheriae/classificação , Corynebacterium diphtheriae/efeitos dos fármacos , Monitoramento Epidemiológico , Cefotaxima/farmacologia , Corynebacterium diphtheriae/genética , Corynebacterium diphtheriae/isolamento & purificação , Difteria/epidemiologia , Eritromicina/farmacologia , Humanos , Índia/epidemiologia , Testes de Sensibilidade Microbiana , Epidemiologia Molecular , Tipagem de Sequências Multilocus , Penicilinas/farmacologia
16.
Microbiol Spectr ; 9(3): e0145521, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34762519

RESUMO

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 Genoma
17.
PLoS One ; 16(11): e0259671, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34780518

RESUMO

The effects of TiO2 nanoparticles (nano-TiO2) together with antibiotics leaking into wastewater treatment plants (WWTPs), especially the partial nitrification (PN) process remain unclear. To evaluate the combined impact and mechanisms of nano-TiO2 and antibiotics on PN systems, batch experiments were carried out with six bench-scale sequencing batch reactors. Nano-TiO2 at a low level had minimal effects on the PN system. In combination with tetracycline and erythromycin, the acute impact of antibiotics was enhanced. Both steps of nitrification were retarded due to the decrease of bacterial activity and abundance, while nitrite-oxidizing bacteria were more sensitive to the inhibition than ammonia-oxidizing bacteria. Proteobacteria at the phylum level and Nitrosospira at the genus level remained predominant under single and combined impacts. The flow cytometry analysis showed that nano-TiO2 enhanced the toxicity of antibiotics through increasing cell permeability. Our results can help clarify the risks of nano-TiO2 combined with antibiotics to PN systems and explaining the behavior of nanoparticles in WWTPs.


Assuntos
Antibacterianos/farmacologia , Nanopartículas Metálicas/química , Titânio/química , Titânio/farmacologia , Eritromicina/farmacologia , Nitritos/química , Nitrosomonadaceae/efeitos dos fármacos , Proteobactérias/efeitos dos fármacos , Tetraciclina/farmacologia , Purificação da Água
18.
Sci Rep ; 11(1): 21737, 2021 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-34741083

RESUMO

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 Jovem
19.
Infect Genet Evol ; 96: 105127, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34718190

RESUMO

The objective of this study was to analyze erythromycin and clindamycin resistance patterns among different MRSA lineages in China. Antimicrobial susceptibility testing, resistance determinant screening, plasmid electroporation and sequence comparisons were performed. High rates of clindamycin (92.5%, 270/292) and erythromycin (92.8%, 271/292) resistance were observed. Additionally, 88.2% (60/68) of the ST59 MRSA isolates and 78.9% (15/19) of the ST239 MRSA isolates had constitutive resistance to clindamycin, while 82.0% (123/150) of the ST5 MRSA isolates showed inducible clindamycin resistance. The ermB gene was identified in 80.9% (55/68) of the ST59 isolates but was not detected in ST5 and ST239 MRSA isolates. Detection rates of ermA were high in the ST5 (99.3%, 149/150) and ST239 (89.5%, 17/19) MRSA isolates, but no ermA-positive ST59 MRSA isolates were identified. The ermC gene, observed to be harbored on similar, transmissible plasmids ranging in size from 2402 to 2473 bp, were found in different MRSA lineages. Summarily, high erythromycin and clindamycin resistance rates were observed in MRSA isolates. ST59 and ST239 MRSA isolates primarily exhibited constitutive resistance, while ST5 MRSA isolates showed inducible resistance phenotypes. ermA and ermB genes were frequently carried by specific MRSA clones, while ermC gene was present within small transmissible plasmids in all lineages. Erythromycin and clindamycin resistance genes transfer between MRSA isolates in healthcare settings remains a problem, and infection control procedures should be applied.


Assuntos
Clindamicina/farmacologia , Farmacorresistência Bacteriana , Eritromicina/farmacologia , Staphylococcus aureus Resistente à Meticilina/genética , Infecções Estafilocócicas/epidemiologia , China/epidemiologia , Genes Bacterianos , Hospitais de Ensino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Infecções Estafilocócicas/microbiologia
20.
Nature ; 599(7883): 120-124, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34646011

RESUMO

Antibiotics are used to fight pathogens but also target commensal bacteria, disturbing the composition of gut microbiota and causing dysbiosis and disease1. Despite this well-known collateral damage, the activity spectrum of different antibiotic classes on gut bacteria remains poorly characterized. Here we characterize further 144 antibiotics from a previous screen of more than 1,000 drugs on 38 representative human gut microbiome species2. Antibiotic classes exhibited distinct inhibition spectra, including generation dependence for quinolones and phylogeny independence for ß-lactams. Macrolides and tetracyclines, both prototypic bacteriostatic protein synthesis inhibitors, inhibited nearly all commensals tested but also killed several species. Killed bacteria were more readily eliminated from in vitro communities than those inhibited. This species-specific killing activity challenges the long-standing distinction between bactericidal and bacteriostatic antibiotic classes and provides a possible explanation for the strong effect of macrolides on animal3-5 and human6,7 gut microbiomes. To mitigate this collateral damage of macrolides and tetracyclines, we screened for drugs that specifically antagonized the antibiotic activity against abundant Bacteroides species but not against relevant pathogens. Such antidotes selectively protected Bacteroides species from erythromycin treatment in human-stool-derived communities and gnotobiotic mice. These findings illluminate the activity spectra of antibiotics in commensal bacteria and suggest strategies to circumvent their adverse effects on the gut microbiota.


Assuntos
Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/classificação , Bactérias/classificação , Bactérias Anaeróbias/efeitos dos fármacos , Bacteroides/efeitos dos fármacos , Clostridioides difficile/efeitos dos fármacos , Dicumarol/farmacologia , Eritromicina/farmacologia , Fezes/microbiologia , Feminino , Vida Livre de Germes , Humanos , Macrolídeos/farmacologia , Masculino , Camundongos , Microbiota/efeitos dos fármacos , Simbiose/efeitos dos fármacos , Tetraciclinas/farmacologia
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