FAMED – Faculdade de Medicina

URI permanente desta comunidadehttps://rihomolog.furg.br/handle/1/2422

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On the search for potential antimycobacterial drugs: synthesis of naphthoquinoidal, phenazinic and 1,2,3-triazolic compounds and evaluation against Mycobacterium tuberculosis
(2015) Jardim, Guilherme Augusto de Melo; Cruz, Eduardo Henrique Guimarães da; Valença, Wagner; Resende, Jarbas Magalhães; Rodrigues, Bernardo Lages; Soares, Daniela Fernandes Ramos; Oliveira, Ronaldo; Silva, Pedro Eduardo Almeida da; Silva Júnior, Eufrânio Nunes da
Fifteen naphthoquinones, sixteen phenazines and fifteen aryl triazoles were synthesized and evaluated against Mycobacterium tuberculosis. Twenty five substances are reported here for the first time and, among all of the compounds evaluated, six presented MIC (minimal inhibitory concentration) values ≤ 6.25 μg mL-1. These substances are promising antimycobacterial prototypes.
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Antimycobacterial activity of usnic acid against resistant and susceptible strains of Mycobacterium tuberculosis and non-tuberculous mycobacteria
(2010) Soares, Daniela Fernandes Ramos; Silva, Pedro Eduardo Almeida da
Tuberculosis remains a serious public health problem, with nine million cases being reported annually. Treatment with antibiotics is the most effective mechanism to control this disease, although the increase in cases with resistant strains, co-infection with HIV, and the long duration of treatment has established the need to develop new drugs. Here we show the activity of usnic acid against susceptible and resistant Mycobacterium tuberculosis strains and against nontuberculous mycobacteria. Further, we did not identify any contribution of efflux in innate resistance to usnic acid.
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Prevalence of tuberculosis in prisons: risk factors and molecular epidemiology
(2015) Valença, Mariana Soares; Scaini, João Luis Rheingantz; Abilleira, Fernanda de Souza; Gonçalves, Carla Vitola; Groll, Andrea Von; Silva, Pedro Eduardo Almeida da
SETTING: Tuberculosis (TB) in prisons is a challenge for the public health system. Active and passive case screening are important tools for TB case detection. OBJECTIVE: To characterise TB in a southern Brazil prison in terms of epidemiological variables, diagnostic approaches and clinical isolate genotypes. DESIGN: Inmates of a southern Brazilian prison were assessed using active and passive TB case screening. Sputum microscopy, culture, drug susceptibility testing and genotyping were performed. Data were analysed using descriptive statistics and multivariable logistic regression. RESULTS: TB prevalence was 4712 per 100 000 inmates, and was associated with low educational level, time incarcerated, productive cough, previous TB history, smoking and human immunodeficiency virus (HIV) infection. Overall, 27.8% of TB cases were detected by culture only; the prevalence of drug-resistant strains was 7.8%; 58.3% of clinical isolates had an identical genotypic profile. CONCLUSION: The study showed extensive circulation of Mycobacterium tuberculosis strains in a highly endemic prison. It is recommended that priority be given to the evaluation of prison inmates with longer jail times, those who are HIV-positive, those with symptoms and those with a previous history of tuberculosis. We observed that active case finding induced passive case detection.
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Prevalence of tuberculosis in prisons: risk factors and molecular epidemiology
(2015) Valença, Mariana Soares; Scaini, João Luis Rheingantz; Abilleira, Fernanda de Souza; Gonçalves, Carla Vitola; Von Groll, Andrea; Silva, Pedro Eduardo Almeida da
SETTING: Tuberculosis (TB) in prisons is a challenge for the public health system. Active and passive case screening are important tools for TB case detection. OBJECTIVE: To characterise TB in a southern Brazil prison in terms of epidemiological variables, diagnostic approaches and clinical isolate genotypes. DESIGN: Inmates of a southern Brazilian prison were assessed using active and passive TB case screening. Sputum microscopy, culture, drug susceptibility testing and genotyping were performed. Data were analysed using descriptive statistics and multivariable logistic regression. RESULTS: TB prevalence was 4712 per 100 000 inmates, and was associated with low educational level, time incarcerated, productive cough, previous TB history, smoking and human immunodeficiency virus (HIV) infection. Overall, 27.8% of TB cases were detected by culture only; the prevalence of drug-resistant strains was 7.8%; 58.3% of clinical isolates had an identical genotypic profile. CONCLUSION: The study showed extensive circulation of Mycobacterium tuberculosis strains in a highly endemic prison. It is recommended that priority be given to the evaluation of prison inmates with longer jail times, those who are HIV-positive, those with symptoms and those with a previous history of tuberculosis. We observed that active case finding induced passive case detection.
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Evaluation of direct microplate nitrate reductase assay as a rapid method for the detection of multiple and extensively tuberculosis drug resistance
(2015) Abilleira, Fernanda de Souza; Brum, Clarice Brinck; Groll, Andrea Von; Silva, Pedro Eduardo Almeida da
Introduction: Reports of Mycobacterium tuberculosis resistant to multiple drugs are increasing globally and laboratories are becoming increasingly aware of the need for drug susceptibility testing. In recent years, due to the long time required by conventional drug susceptibility testing, new approaches have been proposed for faster detection of drug resistance, such as the nitrate reductase assay, considered fast and inexpensive, making it a good diagnostic tool for low resource countries. Objective: The present study proposed a fast direct colorimetric drug susceptibility testing method in a microplate format using solid medium. Materials and methods: The diagnostic accuracy was evaluated by comparing the proportion method with the direct nitrate reductase assay in plates. Frozen sputum samples, known to be positive, were decontaminated and processed by Petroff method. The decontaminated suspension was used to perform direct nitrate reductase assay in 7H11 medium using 1 µg/ml rifampicin (RIF), 0.2 µg/ml isoniazid (INH), 2 µg/ml ofloxacin (OFX), 6 µg/ml kanamycin (KAN), 2 µg/ml amikacin (AMK) and 10 µg/ ml capreomycin (CAP). Eighty-four samples were tested and the results for 69% of them were available within 21 days. Results: The sensitivity and specificity compared to the proportion method, was 98.5% and 100% for INH, 98.3% and 96.2% for RIF, 91.7% and 100% for KAN, 78.8% and 97.3% for OFX, 100% and 100% for AMK and CAP, respectively. Conclusion: The results lead to the conclusion that direct nitrate reductase assay, in this new format, is an accurate, quick and inexpensive method to determine the susceptibility profile of M. tuberculosis and may become an alternative for countries with limited resources.
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Mycobacterium tuberculosis belonging to family LAM and sublineage RDRio: common strains in southern Brazil for over 10 years
(2013) Soares, Renata Oliveira; Macedo, Maíra Bidart de; Groll, Andrea Von; Silva, Pedro Eduardo Almeida da
A sublineage of Mycobacterium tuberculosis called RDRio was described in 2007. Although only recently described, this strain may have been present previously in the population, and its identification in clinical isolates will elucidate bacterial transmission dynamics and host-pathogen interactions. This study evaluated the clonal diversity of the RDRio sublineage in clinical isolates from Rio Grande-RS obtained between 1998 and 2001. Among the 45 samples analyzed by the MIRU-VNTR method, there were six clusters with two samples each and 33 orphan strains with unique pattern. The strains were distributed across several different lineages including LAM (34.04%), X (14.89%), Haarlem (12.77%), UgandaI (10.64%), S (4.26%), NEW-1 (2.13%) and Cameroon (2.13%); 14.89% of the strains matched to multiple lineages. RDRio strains were present in 28.9% of the samples and 81.25% of the identified strains belonged to the LAM family. The high clonal diversity observed in this study is a constant feature in this region. The RDRio sublineage has been in Rio Grande-RS since 1998. The continued monitoring of RDRio in clinical isolates will enhance the understanding of its epidemiological significance.
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Clonal diversity of M. tuberculosis isolated in a sea port city in Brazil
(2009) Silva, Ana Bárbara Scholante; Von Groll, Andrea; Felix, Carolina Rodrigues; Conceição, Fabricio Rochedo; Spies, Fernanda Sá; Scaini, Carlos James; Rossetti, Maria Lucia Rosa; Borsuk, Sibele; Dellagostin, Odir Antonio; Silva, Pedro Eduardo Almeida da
Genotyping tools have been widely used to study the occurrence of outbreaks and to identify the patterns of transmission of Mycobacterium tuberculosis strains. The clonal diversity of 65 clinical isolates of M. tuberculosis was determined by PCR methods. The Double Repeat Element method (DRE-PCR) and spoligotyping identified 45 and 26 distinct patterns respectively. Among these, LAM (38%) was the most frequent lineage, followed by Haarlem (31%) and T (20%). Five orphan patterns were not present in the SITVIT database. Mycobacterial interspersed repetitive units (MIRU) using 12 loci revealed 46 distinct patterns. MIRU loci 10, 23, 26 and 40 had the highest discriminatory power. The high genetic diversity found among M. tuberculosis isolates in this study suggests a high level of recent TB transmission, indicating an endemic mode of TB transmission and a putative importation of new TB genotypes. In addition, the high diversity among the isolates could indicate early detection of the infection in patients and an efficient rate of cure.
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Sequence and structural characterization of tbnat gene in isoniazid-resistant Mycobacterium tuberculosis: identification of new mutations
(2011) Coelho, Millene Borges; Dalla Costa, Elis Regina; Vasconcellos, Sidra Ezídio Gonçalves; Linck, Natali Tejada; Ramos, Ricardo Martins; Amorim, Hermes Luís Neubauer de; Suffys, Philip Noel; Santos, Adalberto Rezende; Silva, Pedro Eduardo Almeida da; Soares, Daniela Fernandes Ramos; Silva, Márcia Susana Nunes; Rossetti, Maria Lucia Rosa
The present study was carried out to investigate the presence of polymorphism in the N-acetyltransferase gene of 41 clinical isolates of Mycobacterium tuberculosis, that were resistant to isoniazid (INH) with no mutations in the hot spots of the genes previously described to be involved in INH resistance (katG, inhA and ahpC). We observed single nucleotide polymorphisms (SNPs) in ten of these, including the G619A SNP in five isolates and an additional four so far un-described mutations in another five isolates. Among the latter SNPs, two were synonymous (C276T, n = 1 and C375G, n = 3), while two more non-synonymous SNPs were composed of C373A (Leu→Met) and T503G (Met→Arg) were observed in respectively one and two isolates. Molecular modeling and structural analysis based in a constructed full length 3D models of wild type TBNAT (TBNAT H37Rv) and the isoforms (TBNAT L125M and TBNAT M168R) were also performed. The refined models show that, just as observed in human NATs, the carboxyl terminus extends deep within the folded enzyme, into close proximity to the buried catalytic triad. Analysis of tbnat that present non-synonymous mutations indicates that both substitutions are plausible to affect enzyme specificity or acetyl-CoA binding capacity. The results contribute to a better understanding of structure–function relationships of NATs. However, further investigation including INH-sensitive strains as a control group is needed to get better understanding of the possible role of these new mutations on tuberculosis control.
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Improving tuberculosis control through the partnership between university and the health system
(2012) Valença, Mariana Soares; Rocha, Jeane Zanini da; Ramis, Ivy Bastos; Carrion, Lillian Lucas; Madruga, Catiúcia Figueiredo Goris; Macedo, Maíra Bidart de; Scaini, Carlos James; Groll, Andrea Von; Silva, Pedro Eduardo Almeida da
Tuberculosis (TB) control is linked to the availability of qualified methods for microbiological diagnostics; however, microscopy with limited sensitivity is the only method available in many locations. The objective of this study was to evaluate the introduction of culture, drug susceptibility testing (DST), and genotyping in the routine of a Municipal Program of Tuberculosis Control. Methods: Direct microscopy of sputum and culture in Ogawa-Kudoh were performed on 1,636 samples from 787 patients. DST of positive cultures was performed by resazurin microtiter assay and genotyping by mycobacterial interspersed repetitive units–variable number tandem repeat. Results: A total 91 patients with TB were identified. The culture increased case detection by 32% compared with the microscopy; acquired resistance was 3.3% and the genotyping showed high genetic diversity. Conclusions: Ogawa-Kudoh contributed significantly to the increase in case detection and is suitable for implementation in poor-resource locations. The acquired resistance rate was lower than that reported in a recent Brazilian survey. The high genetic diversity is possibly related to the high TB prevalence in the population, as well as to early detection and suitable treatment of patients. The interaction between research and health care is important for reorienting the practice, transferring technology, and improving TB control.
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Synthesis and antituberculosis activity of new fatty acid amides
(2010) D'Oca, Caroline Da Ros Montes; Coelho, Tatiane Silveira; Marinho, Tamara Germani; Hack, Carolina Rosa Lopes; Duarte, Rodrigo da Costa; Silva, Pedro Eduardo Almeida da; D'Oca, Marcelo Gonçalves Montes
This work reports the synthesis of new fatty acid amides from C16:0, 18:0, 18:1, 18:1 (OH), and 18:2 fatty acids families with cyclic and acyclic amines and demonstrate for the first time the activity of these compounds as antituberculosis agents against Mycobacterium tuberculosis H37Rv, M. tuberculosis rifampicin resistance (ATCC 35338), and M. tuberculosis isoniazid resistance (ATCC 35822). The fatty acid amides derivate from ricinoleic acid were the most potent one among a series of tested compounds, with a MIC 6.25 lg/mL for resistance strains.

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