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1.
Science ; 371(6534): 1154-1159, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33707263

RESUMO

Alterations of the mycobiota composition associated with Crohn's disease (CD) are challenging to link to defining elements of pathophysiology, such as poor injury repair. Using culture-dependent and -independent methods, we discovered that Debaryomyces hansenii preferentially localized to and was abundant within incompletely healed intestinal wounds of mice and inflamed mucosal tissues of CD human subjects. D. hansenii cultures from injured mice and inflamed CD tissues impaired colonic healing when introduced into injured conventionally raised or gnotobiotic mice. We reisolated D. hansenii from injured areas of these mice, fulfilling Koch's postulates. Mechanistically, D. hansenii impaired mucosal healing through the myeloid cell-specific type 1 interferon-CCL5 axis. Taken together, we have identified a fungus that inhabits inflamed CD tissue and can lead to dysregulated mucosal healing.


Assuntos
Doença de Crohn/microbiologia , Doença de Crohn/patologia , Debaryomyces/isolamento & purificação , Debaryomyces/fisiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Anfotericina B/farmacologia , Animais , Antibacterianos/farmacologia , Antifúngicos/farmacologia , Quimiocina CCL5/metabolismo , Colo/microbiologia , Colo/patologia , Doença de Crohn/imunologia , Debaryomyces/crescimento & desenvolvimento , Feminino , Microbioma Gastrointestinal , Vida Livre de Germes , Humanos , Íleo/microbiologia , Íleo/patologia , Inflamação , Interferon Tipo I/metabolismo , Mucosa Intestinal/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
3.
Diagn Microbiol Infect Dis ; 100(1): 115325, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33556650

RESUMO

Although multidrug therapy is considered an effective treatment for leprosy, antimicrobial resistance is a serious concern. We performed a systematic review of studies on the diagnostic accuracy and screening of tests for antimicrobial resistance in leprosy. This review was registered in PROSPERO (CRD42020177958). In April 2020, we searched for studies in the PubMed, EMBASE, Web of Science, Scopus, Scielo, and LILACS databases. A random effects regression model was used for the meta-analysis. We included 129 studies. Molecular tests for dapsone resistance had a sensitivity of 78.8% (95% confidence interval [CI] = 65.6-87.9) and a specificity of 97.0% (95% CI = 94.0-98.6). Molecular tests for rifampicin resistance had a sensitivity and specificity of 88.7% (95% CI = 80.0-93.9) and 97.3% (95% CI = 94.3-98.8), respectively. Molecular tests for ofloxacin resistance had a sensitivity and specificity of 80.9% (95% CI = 60.1-92.3) and 96.1% (95% CI = 90.2-98.5), respectively. In recent decades, no increase in the resistance proportion was detected. However, the growing number of resistant cases is still a clinical concern.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Hanseníase , Testes de Sensibilidade Microbiana , Mycobacterium leprae/efeitos dos fármacos , DNA Bacteriano/genética , Humanos , Hanseníase/diagnóstico , Hanseníase/microbiologia , Testes de Sensibilidade Microbiana/métodos , Testes de Sensibilidade Microbiana/normas , Sensibilidade e Especificidade , Análise de Sequência de DNA
4.
Artigo em Inglês | MEDLINE | ID: mdl-33361310

RESUMO

Mycobacteroides abscessus (Mab) is an opportunistic environmental pathogen that can cause chronic pulmonary disease in the setting of structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. These infections are often incurable and associated with rapid lung function decline. Mab is naturally resistant to most of the antibiotics available today, and current treatment guidelines require at least 1 year of daily multidrug therapy, which is often ineffective and is associated with significant toxicities. ß-Lactams are the most widely used class of antibiotics and have a demonstrated record of safety and tolerability. Here, using a panel of recent clinical isolates of Mab, we evaluated the in vitro activities of dual-ß-lactam combinations to identify new treatments with the potential to treat infections arising from a wide range of Mab strains. The Mab clinical isolates were heterogeneous, as reflected by the diversity of their genomes and differences in their susceptibilities to various drugs. Cefoxitin and imipenem are currently the only two ß-lactams included in the guidelines for treating Mab disease, yet they are not used concurrently in clinical practice. However, this dual-ß-lactam combination exhibited synergy against 100% of the isolates examined (n = 21). Equally surprising is the finding that the combination of two carbapenems, doripenem and imipenem, exhibited synergy against the majority of Mab isolates. In the setting of multidrug-resistant Mab disease with few therapeutic options, these combinations may offer viable immediate treatment options with efficacy against the broad spectrum of Mab strains infecting patients today.


Assuntos
Mycobacterium abscessus , Antibacterianos/farmacologia , Quimioterapia Combinada , Humanos , Hansenostáticos , Testes de Sensibilidade Microbiana , beta-Lactamas/farmacologia
5.
BMC Res Notes ; 13(1): 455, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993780

RESUMO

OBJECTIVE: Lyme disease is a tick-borne, multisystemic disease caused by Borrelia burgdorferi. Standard treatments for early Lyme disease include short courses of oral antibiotics but relapses often occur after discontinuation of treatment. Several studies have suggested that ongoing symptoms may be due to a highly antibiotic resistant form of B. burgdorferi called biofilms. Our recent clinical study reported the successful use of an intracellular mycobacterium persister drug used in treating leprosy, diaminodiphenyl sulfone (dapsone), in combination therapy for the treatment of Lyme disease. In this in vitro study, we evaluated the effectiveness of dapsone individually and in combination with cefuroxime and/or other antibiotics with intracellular activity including doxycycline, rifampin, and azithromycin against Borrelia biofilm forms utilizing crystal violet biofilm mass, and dimethyl methylene blue glycosaminoglycan assays combined with Live/Dead fluorescent microscopy analyses. RESULTS: Dapsone, alone or in various combinations with doxycycline, rifampin and azithromycin produced a significant reduction in the mass and protective glycosaminoglycan layer and overall viability of B. burgdorferi biofilm forms. This in vitro study strongly suggests that dapsone combination therapy could represent a novel and effective treatment option against the biofilm form of B. burgdorferi.


Assuntos
Borrelia burgdorferi , Doença de Lyme , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Biofilmes , Dapsona/farmacologia , Humanos , Doença de Lyme/tratamento farmacológico
6.
Int J Mol Sci ; 21(17)2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867307

RESUMO

Outside of Mycobacterium tuberculosis and Mycobacterium leprae, nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.


Assuntos
Antibacterianos/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas/metabolismo , Antibacterianos/uso terapêutico , Proteínas de Bactérias/metabolismo , Transporte Biológico/efeitos dos fármacos , Descoberta de Drogas , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Iodóforos/farmacologia , Iodóforos/uso terapêutico , Isoxazóis/farmacologia , Isoxazóis/uso terapêutico , Infecções por Mycobacterium não Tuberculosas/metabolismo , Ácidos Micólicos/metabolismo , Micobactérias não Tuberculosas/efeitos dos fármacos , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico
7.
Nucleic Acids Res ; 48(14): 8099-8112, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32602532

RESUMO

Translational frameshift errors are often deleterious to the synthesis of functional proteins and could therefore be promoted therapeutically to kill bacteria. TrmD (tRNA-(N(1)G37) methyltransferase) is an essential tRNA modification enzyme in bacteria that prevents +1 errors in the reading frame during protein translation and represents an attractive potential target for the development of new antibiotics. Here, we describe the application of a structure-guided fragment-based drug discovery approach to the design of a new class of inhibitors against TrmD in Mycobacterium abscessus. Fragment library screening, followed by structure-guided chemical elaboration of hits, led to the rapid development of drug-like molecules with potent in vitro TrmD inhibitory activity. Several of these compounds exhibit activity against planktonic M. abscessus and M. tuberculosis as well as against intracellular M. abscessus and M. leprae, indicating their potential as the basis for a novel class of broad-spectrum mycobacterial drugs.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , RNA de Transferência/metabolismo , tRNA Metiltransferases/antagonistas & inibidores , Antibacterianos/química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Descoberta de Drogas/métodos , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/enzimologia , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/enzimologia , Ligação Proteica , tRNA Metiltransferases/química , tRNA Metiltransferases/metabolismo
8.
Expert Rev Clin Pharmacol ; 13(4): 391-401, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32310683

RESUMO

INTRODUCTION: Pharmacological treatment of Buruli ulcer (Mycobacterium ulcerans infection; BU) is highly effective, as shown in two randomized trials in Africa. AREAS COVERED: We review BU drug treatment - in vitro, in vivo and clinical trials (PubMed: '(Buruli OR (Mycobacterium AND ulcerans)) AND (treatment OR therapy).' We also highlight the pathogenesis of M. ulcerans infection that is dominated by mycolactone, a secreted exotoxin, that causes skin and soft tissue necrosis, and impaired immune response and tissue repair. Healing is slow, due to the delayed wash-out of mycolactone. An array of repurposed tuberculosis and leprosy drugs appears effective in vitro and in animal models. In clinical trials and observational studies, only rifamycins (notably, rifampicin), macrolides (notably, clarithromycin), aminoglycosides (notably, streptomycin) and fluoroquinolones (notably, moxifloxacin, and ciprofloxacin) have been tested. EXPERT OPINION: A combination of rifampicin and clarithromycin is highly effective but lesions still take a long time to heal. Novel drugs like telacebec have the potential to reduce treatment duration but this drug may remain unaffordable in low-resourced settings. Research should address ulcer treatment in general; essays to measure mycolactone over time hold promise to use as a readout for studies to compare drug treatment schedules for larger lesions of Buruli ulcer.


Assuntos
Antibacterianos/farmacologia , Úlcera de Buruli/tratamento farmacológico , Mycobacterium ulcerans/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Úlcera de Buruli/microbiologia , Reposicionamento de Medicamentos , Quimioterapia Combinada , Humanos , Macrolídeos/metabolismo , Mycobacterium ulcerans/isolamento & purificação , Ensaios Clínicos Controlados Aleatórios como Assunto , Cicatrização/efeitos dos fármacos
9.
Med Sci Monit ; 26: e920879, 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986127

RESUMO

BACKGROUND Debaryomyces hansenii exhibits a therapeutic effect on antibiotic-associated diarrhea (AAD) by promoting the growth of beneficial intestinal bacteria. Previous research has reported that AAD involves not only dysbacteriosis but also dysfunction of the activity of intestinal enzymes (such as lactase). Enzyme activities can be influenced by many other factors, such as gene expression. The present study showed that D. hansenii has a curative effect on AAD at the lactase gene level. MATERIAL AND METHODS The effect of D. hansenii on the lactase gene from intestinal bacteria in AAD mice was investigated. The diarrhea model was established with a gentamycin sulfate and cefradine capsule mixture. The antibiotic mixture (23.33 mL·kg⁻¹·day⁻¹) was intragastrically administered for 5 days. Subsequently, half of the diarrhea mice were treated with D. hansenii twice a day for 3 days while the other mice were intragastrically administered with the same volume of distilled water. Next, the intestinal contents were collected, and metagenomic DNA was extracted for high-throughput sequencing analysis. RESULTS The Chao1 and Shannon indices decreased significantly following treatment with D. hansenii (P<0.01 and P<0.05, respectively). Moreover, the clusters in the D. hansenii group mice were quite different from those in the normal group mice and model group mice. Following treatment with D. hansenii, the quantity of lactase genes in Enterobacter sp. 638 and Modestobacter increased markedly, and the richness of intestinal bacterial lactase genes in Fretibacterium recovered. CONCLUSIONS D. hansenii altered the lactase-producing bacterial community structure and promoted the growth of several critical lactase-producing bacteria, such as Enterobacter sp. 638 and Modestobacter.


Assuntos
Antibacterianos/uso terapêutico , Bactérias/genética , Biodiversidade , Diarreia/tratamento farmacológico , Diarreia/microbiologia , Genes Bacterianos , Intestinos/microbiologia , Lactase/genética , Animais , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Sequência de Bases , Feminino , Masculino , Camundongos
10.
J Antimicrob Chemother ; 75(3): 609-617, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31886864

RESUMO

BACKGROUND: Pulmonary infections caused by non-tuberculous mycobacteria (NTM) are hard to treat and have low cure rates despite intensive multidrug therapy. OBJECTIVES: To assess the feasibility of tedizolid, a new oxazolidinone, for the treatment of Mycobacterium avium and Mycobacterium abscessus. METHODS: We determined MICs of tedizolid for 113 isolates of NTM. Synergy with key antimycobacterial drugs was assessed using the chequerboard method and calculation of the FIC index (FICI). We performed time-kill kinetics assays of tedizolid alone and combined with amikacin for M. abscessus and with ethambutol for M. avium. Human macrophages were infected with M. abscessus and M. avium and subsequently treated with tedizolid; intracellular and extracellular cfu were quantified over time. RESULTS: NTM isolates generally had a lower MIC of tedizolid than of linezolid. FICIs were lowest between tedizolid and amikacin for M. abscessus (FICI = 0.75) and between tedizolid and ethambutol for M. avium (FICI = 0.72). Clarithromycin and tedizolid showed initial synergy, which was abrogated by erm(41)-induced macrolide resistance (FICI = 0.53). Tedizolid had a weak bacteriostatic effect on M. abscessus and combination with amikacin slightly prolonged its effect. Tedizolid had concentration-dependent activity against M. avium and its efficacy was enhanced by ethambutol. Both combinations had a concentration-dependent synergistic effect. Tedizolid could inhibit the intracellular bacterial population of both M. avium and M. abscessus. CONCLUSIONS: Tedizolid should be further investigated in pharmacodynamic studies and clinical trials for M. avium complex pulmonary disease. It is less active against M. abscessus, but still promising.


Assuntos
Infecções por Mycobacterium não Tuberculosas , Oxazolidinonas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Quimioterapia Combinada , Humanos , Hansenostáticos , Macrolídeos/uso terapêutico , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Micobactérias não Tuberculosas , Oxazolidinonas/uso terapêutico , Tetrazóis
11.
J Infect Chemother ; 26(4): 335-342, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31839561

RESUMO

BACKGROUND: Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin. METHODOLOGY/PRINCIPAL FINDINGS: Here we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico. Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead. CONCLUSIONS/SIGNIFICANCE: The inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.


Assuntos
Antibacterianos/farmacologia , Azetidinas/farmacologia , DNA Girase/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Mycobacterium leprae/efeitos dos fármacos , Antibacterianos/uso terapêutico , Azetidinas/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/uso terapêutico , Humanos , Hanseníase/tratamento farmacológico , Testes de Sensibilidade Microbiana , Ofloxacino/farmacologia
12.
PLoS One ; 14(11): e0224730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31725747

RESUMO

AIM: To confirm the effects of Debaryomyces hansenii on intestinal microecology in mice with antibiotic-associated diarrhea (AAD). METHODS: This study took the mucosal microecology as the entry point and an antibiotic mixture was used to induce diarrhea in mice. D. hansenii suspension was used to treat the mice and the bacterial communities of mucosa was analyzed using high-throughput sequencing. RESULTS: The Shannon-Wiener index indicated that the sequencing depth is reasonable and reflected the majority of microbial information. The principal coordinate analysis results showed that mice in the treatment group and the normal group had a similar microbial community structure, while differences in microbial community structure were observed between the model group and the treatment group. The inter-group bacterial structures were analyzed at the phylum level and genus level. The results revealed that antibiotic treatment increased the proportion of Proteobacteria and decreased the proportion of Bacteroides, while D. hansenii treatment inhibited the increase in Proteobacteria. Linear discriminant analysis coupled with effect size measurements (LEfSe) suggested d that the beneficial bacteria Candidatus Arthromitus were the only common bacteria in the normal group (P<0.05). CONCLUSION: The treatment with D.hansenii could contribute to the maintenance of the structure of the mucosal microbiota in comparison with the normal group and inhibit the proliferation of opportunistic bacteria. However, high-dose antibiotic treatment causes mucosal dysbiosis and the proliferation of opportunistic bacteria during the self-recovery period, such as Pseudoalteromonas, Alteromonas, Vibrio.


Assuntos
Antibacterianos/efeitos adversos , Bactérias/crescimento & desenvolvimento , Debaryomyces , Diarreia , Disbiose , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Antibacterianos/farmacologia , Bactérias/classificação , Diarreia/induzido quimicamente , Diarreia/microbiologia , Diarreia/terapia , Disbiose/induzido quimicamente , Disbiose/microbiologia , Disbiose/terapia , Camundongos
13.
Indian J Dermatol Venereol Leprol ; 85(5): 441-447, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31389367

RESUMO

Despite adequate treatment of reproductive tract infection, there is persistence of symptoms in some patients. This raises the possibility of existence of other silent microbes with pathogenic potential. Apart from the common sexually transmitted organisms such as Chlamydia trachomatis and Neisseria gonorrhoeae, there are other silent and emerging pathogens, like genital mycoplasma, which have been associated with cervicitis, pelvic inflammatory disease, infertility, and pregnancy-related complications in women. Although these organisms were identified decades ago, they are still overlooked or ignored. There is a need to understand the role played by these organisms in Asian populations and their susceptibility to the standard line of treatment. Data on genital mycoplasma infections in Indian women is heterogeneous, with limited evidence of pathogenicity. Although known for their wide spectrum of reproductive morbidities in western counterparts, these microorganisms are yet to gain the attention of Indian clinicians and microbiologists. There is paucity of adequate information in India regarding these infections, so Indian literature was compiled to get an overview of these pathogens, their association with reproductive morbidities, and their response to treatment. Thus, there is a need to explore genital mycoplasma infections in Indian women, especially in the arena of antimicrobial resistance among genital mycoplasma, which has the potential to become a major problem. A literature search with keywords focusing on "genital mycoplasma", "sexually transmitted infections India", "sexually transmitted mycoplasma", and "characteristic of mycoplasma" was carried out through computerized databases like PubMed, MEDLINE, Embase, and Google Scholar.


Assuntos
Doenças dos Genitais Femininos/epidemiologia , Infecções por Mycoplasma/epidemiologia , Doenças Sexualmente Transmissíveis/epidemiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/fisiologia , Feminino , Doenças dos Genitais Femininos/diagnóstico , Doenças dos Genitais Femininos/terapia , Humanos , Índia/epidemiologia , Infecções por Mycoplasma/diagnóstico , Infecções por Mycoplasma/terapia , Prevalência , Doenças Sexualmente Transmissíveis/diagnóstico , Doenças Sexualmente Transmissíveis/terapia , Resultado do Tratamento
14.
J Med Microbiol ; 68(10): 1438-1444, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385784

RESUMO

Introduction. Combretum leprosum (Combretaceae) is commonly found in the Northeast Region of Brazil and is known for several bioactivities, including antimicrobial ones. Because of increasing bacterial antibiotic resistance, natural products from several plants have been studied as putative adjuvants to antibiotic activity, including products from C. leprosum. Aims. This study was carried out to investigate the structural properties, bactericidal activity and antibiotic modifying action of the lupane triterpene 3ß,6ß,16ß-trihydroxylup-20(29)-ene (CLF1) isolated from C. leprosum Mart. leaves.Methods. The CLF1 was evaluated by the Fourier transform infrared spectroscopy method and the antibacterial activity of this compound was assayed alone and in association with antibiotics by microdilution assay.Results. Spectroscopic studies confirmed the molecular structure of the CLF1 and permitted assignment of the main infrared bands of this natural product. Microbiological assays showed that this lupane triterpene possesses antibacterial action with clinical relevance against Staphylococcus aureus. The CLF1 triterpene increased antimicrobial activity against the multidrug-resistant Escherichia coli 06 strain when associated with the antibiotics gentamicin and amikacin. Synergistic effects were observed against the S. aureus 10 strain in the presence of the CLF1 triterpene with the antibiotic gentamicin.Conclusion. In conclusion, the CLF1 compound may be useful in the development of antibacterial drugs against the aforementioned bacteria.


Assuntos
Antibacterianos/farmacologia , Combretum/química , Extratos Vegetais/farmacologia , Triterpenos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Brasil , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Gentamicinas/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Triterpenos/química , Triterpenos/isolamento & purificação
15.
An Acad Bras Cienc ; 91(3): e20180404, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365649

RESUMO

In this study, the antimicrobial, antioxidant and antitumor activity of ethanol extracts obtained from Phlomis russeliana (Sims.) Lag. ex Benth. (Lamiaceae) were evaluated. Disc diffusion and microdilution methods were used to test the extracts for antimicrobial activity against seven bacteria strains (Bacillus cereus ATCC 7064, Bacillus subtilis ATCC 6633, Staphylococcus aureus ATCC 6538P, Escherichia coli ATCC 10538, Proteus vulgaris ATCC 6899, Salmonella typhimurium CCM 5445 and Pseudomonas aeruginosa ATCC 27853) and four yeast strains (Kluyveromyces fragilis ATCC 8608, Rhodotorula rubra ATCC 70403, Debaryomyces hansenii DSM 70238 and Candida albicans ATCC 10239). Notably, they were more effective against the yeast strains than the bacterial strains. Of the yeast cultures, D. hanseii was among the most susceptible, having an inhibition zone of 16.2 mm with minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs) of 64(128)µg/ml, respectively. For cytotoxic determination, Caco-2 cells were cultured as per ATCC protocol, and were treated with log concentrations (5-80 mg/ml) of P. russeliana. The potency of cell growth inhibition for each extract was expressed as an IC50 value. Moreover, oxidant capacity was evaluated via TOC assay. This product induced antiproliferative activity of 31.33% at 40 mg/ml and 20.96% at 80 mg/ml, without toxic effects on cells, although the oxidant capacity was decreased to 27.06 ± 0.7 nm in the 80 mg/ml-applied group compared to 47.9 ± 1.8 nm in the untreated one. Advanced pharmacological studies are needed to further evaluate P. russeliana for distinctive features.


Assuntos
Antibacterianos/farmacologia , Antioxidantes/farmacologia , Candida albicans/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Phlomis/química , Extratos Vegetais/farmacologia , Antibacterianos/isolamento & purificação , Antioxidantes/isolamento & purificação , Células CACO-2 , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Bactérias Gram-Negativas/classificação , Bactérias Gram-Positivas/classificação , Humanos , Turquia
16.
J Med Chem ; 62(15): 7210-7232, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282680

RESUMO

Mycobacterium abscessus (Mab) is a rapidly growing species of multidrug-resistant nontuberculous mycobacteria that has emerged as a growing threat to individuals with cystic fibrosis and other pre-existing chronic lung diseases. Mab pulmonary infections are difficult, or sometimes impossible, to treat and result in accelerated lung function decline and premature death. There is therefore an urgent need to develop novel antibiotics with improved efficacy. tRNA (m1G37) methyltransferase (TrmD) is a promising target for novel antibiotics. It is essential in Mab and other mycobacteria, improving reading frame maintenance on the ribosome to prevent frameshift errors. In this work, a fragment-based approach was employed with the merging of two fragments bound to the active site, followed by structure-guided elaboration to design potent nanomolar inhibitors against Mab TrmD. Several of these compounds exhibit promising activity against mycobacterial species, including Mycobacterium tuberculosis and Mycobacterium leprae in addition to Mab, supporting the use of TrmD as a target for the development of antimycobacterial compounds.


Assuntos
Antibacterianos/química , Desenvolvimento de Medicamentos/métodos , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/metabolismo , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/enzimologia , tRNA Metiltransferases/antagonistas & inibidores , tRNA Metiltransferases/metabolismo , Antibacterianos/farmacologia , Cristalografia por Raios X/métodos , Humanos , Estrutura Secundária de Proteína
17.
J Clin Microbiol ; 57(8)2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31092597

RESUMO

Many pathogens that caused devastating disease throughout human history, such as Yersinia pestis, Mycobacterium tuberculosis, and Mycobacterium leprae, remain problematic today. Historical bacterial genomes represent a unique source of genetic information and advancements in sequencing technologies have allowed unprecedented insights from this previously understudied resource. This minireview brings together example studies which have utilized ancient DNA, individual historical isolates (both extant and dead) and collections of historical isolates. The studies span human history and highlight the contribution that sequencing and analysis of historical bacterial genomes have made to a wide variety of fields. From providing retrospective diagnosis, to uncovering epidemiological pathways and characterizing genetic diversity, there is clear evidence for the utility of historical isolate studies in understanding disease today. Studies utilizing historical isolate collections, such as those from the National Collection of Type Cultures, the American Type Culture Collection, and the Institut Pasteur, offer enhanced insight since they typically span a wide time period encompassing important historical events and are useful for the investigating the phylodynamics of pathogens. Furthermore, historical sequencing studies are particularly useful for looking into the evolution of antimicrobial resistance, a major public health concern. In summary, although there are limitations to working with historical bacterial isolates, especially when utilizing ancient DNA, continued improvement in molecular and sequencing technologies and the resourcefulness of investigators mean this area of study will continue to expand and contribute to the understanding of pathogens.


Assuntos
Bactérias/genética , DNA Antigo/análise , Genoma Bacteriano , Análise de Sequência de DNA , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/patogenicidade , Farmacorresistência Bacteriana Múltipla/genética , Evolução Molecular , Variação Genética , Humanos , Mycobacterium leprae/genética , Mycobacterium leprae/patogenicidade , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidade , Filogenia , Yersinia pestis/genética , Yersinia pestis/patogenicidade
18.
Parasit Vectors ; 12(1): 237, 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31097026

RESUMO

The survival of spirochetes from the Borrelia burgdorferi (sensu lato) complex in a hostile environment is achieved by the regulation of differential gene expression in response to changes in temperature, salts, nutrient content, acidity fluctuation, multiple host or vector dependent factors, and leads to the formation of dormant subpopulations of cells. From the other side, alterations in the level of gene expression in response to antibiotic pressure leads to the establishment of a persisters subpopulation. Both subpopulations represent the cells in different physiological states. "Dormancy" and "persistence" do share some similarities, e.g. both represent cells with low metabolic activity that can exist for extended periods without replication, both constitute populations with different gene expression profiles and both differ significantly from replicating forms of spirochetes. Persisters are elusive, present in low numbers, morphologically heterogeneous, multi-drug-tolerant cells that can change with the environment. The definition of "persisters" substituted the originally-used term "survivors", referring to the small bacterial population of Staphylococcus that survived killing by penicillin. The phenomenon of persisters is present in almost all bacterial species; however, the reasons why Borrelia persisters form are poorly understood. Persisters can adopt varying sizes and shapes, changing from well-known forms to altered morphologies. They are capable of forming round bodies, L-form bacteria, microcolonies or biofilms-like aggregates, which remarkably change the response of Borrelia to hostile environments. Persisters remain viable despite aggressive antibiotic challenge and are able to reversibly convert into motile forms in a favorable growth environment. Persisters are present in significant numbers in biofilms, which has led to the explanation of biofilm tolerance to antibiotics. Considering that biofilms are associated with numerous chronic diseases through their resilient presence in the human body, it is not surprising that interest in persisting cells has consequently accelerated. Certain diseases caused by pathogenic bacteria (e.g. tuberculosis, syphilis or leprosy) are commonly chronic in nature and often recur despite antibiotic treatment. Three decades of basic and clinical research have not yet provided a definite answer to the question: is there a connection between persisting spirochetes and recurrence of Lyme disease in patients?


Assuntos
Antibacterianos/farmacologia , Grupo Borrelia Burgdorferi/fisiologia , Doença de Lyme/microbiologia , Viabilidade Microbiana/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Grupo Borrelia Burgdorferi/efeitos dos fármacos , Humanos , Recidiva
19.
Appl Environ Microbiol ; 85(4)2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30530711

RESUMO

A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there have been dozens of successful cases facilitated by the development of genomic sequencing. During our study on biosynthesis of the antitumor polyketide kosinostatin (KST), we found that the genome of Micromonospora sp. strain TP-A0468, the producer of KST, contains other potential polyketide gene clusters, with no encoded products detected. Deletion of kst cluster led to abolishment of KST and the enrichment of several new compounds, which were isolated and characterized as 16-demethylrifamycins (referred to here as compounds 3 to 6). Transcriptional analysis demonstrated that the expression of the essential genes related to the biosynthesis of compounds 3 to 6 was comparable to the level in the wild-type and in the kst cluster deletion strain. This indicates that the accumulation of these compounds was due to the redirection of metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, and bioinformatic analysis revealed that the production of compounds 3 to 6 was accomplished by cross talk between the two distantly placed polyketide gene clusters pks3 and M-rif This finding not only enriches the analogue pool and the biosynthetic diversity of rifamycins but also provides an auxiliary strategy for natural product discovery through genome mining in polyketide-producing microorganisms.IMPORTANCE Natural products are essential in the development of novel clinically used drugs. Discovering new natural products and modifying known compounds are still the two main ways to generate new candidates. Here, we have discovered several rifamycins with varied skeleton structures by redirecting the metabolic flux from the predominant polyketide biosynthetic pathway to the rifamycin pathway in the marine actinomycetes species Micromonospora sp. strain TP-A0468. Rifamycins are indispensable chemotherapeutics in the treatment of various diseases such as tuberculosis, leprosy, and AIDS-related mycobacterial infections. This study exemplifies a useful method for the discovery of cryptic natural products in genome-sequenced microbes. Moreover, the 16-demethylrifamycins and their genetically manipulable producer provide a new opportunity in the construction of novel rifamycin derivates to aid in the defense against the ever-growing drug resistance of Mycobacterium tuberculosis.


Assuntos
Aminoglicosídeos/biossíntese , Aminoglicosídeos/genética , Antibacterianos/biossíntese , Antibacterianos/farmacologia , Descoberta de Drogas , Micromonospora/genética , Micromonospora/metabolismo , Aminoglicosídeos/farmacologia , Sequência de Bases , Vias Biossintéticas/genética , Deleção de Genes , Lactamas Macrocíclicas/metabolismo , Família Multigênica/genética , Policetídeos/metabolismo , Rifamicinas/biossíntese , Metabolismo Secundário/genética
20.
Semin Cell Dev Biol ; 73: 165-176, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28668355

RESUMO

Antimicrobial molecules have been used for more than 50 years now and are the basis of modern medicine. No surgery can nowdays be imagined to be performed without antibiotics; dreadful diseases like tuberculosis, leprosis, siphilys, and more broadly all microbial induced diseases, can be cured only through the use of antimicrobial treatments. However, the situation is becoming more and more complex because of the ability of microbes to adapt, develop, acquire, and share mechanisms of resistance to antimicrobial agents. We choose to introduce this review by briefly drawing the panorama of antimicrobial discovery and development, but also of the emergence of microbial resistance. Then we describe how Atomic Force Microscopy (AFM) can be used to provide a better understanding of the mechanisms of action of these drugs at the nanoscale level on microbial interfaces. In this section, we will address these questions: (1) how does drug treatment affect the morphology of single microbes?; (2) do antimicrobial molecules modify the nanomechanical properties of microbes, or do the nanomechanical properties of microbes play a role in antimicrobial activity and efficiency?; and (3) how are the adhesive abilitites of microbes affected by antimicrobial drugs treatment? Finally, in a second part of this review we focus on recent studies aimed at changing the paradigm of the single molecule/cell technology that AFM typically represents. Recent work dealing with the creation of a microbe array which can be explored by AFM will be presented, as these developments constitute the first steps toward transforming AFM into a higher throughput technology. We also discuss papers using AFM as NanoMechnanicalSensors (NEMS), and demonstrate the interest of such approaches in clinical microbiology to detect quickly and with high accuracy microbial resistance.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/ultraestrutura , Microscopia de Força Atômica , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/ultraestrutura , Antibacterianos/química , Antifúngicos/química , Bactérias/citologia , Nanotecnologia , Saccharomyces cerevisiae/citologia
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