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2.
Nature ; 571(7763): 72-78, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31217586

RESUMO

New antibiotics are needed to combat rising levels of resistance, with new Mycobacterium tuberculosis (Mtb) drugs having the highest priority. However, conventional whole-cell and biochemical antibiotic screens have failed. Here we develop a strategy termed PROSPECT (primary screening of strains to prioritize expanded chemistry and targets), in which we screen compounds against pools of strains depleted of essential bacterial targets. We engineered strains that target 474 essential Mtb genes and screened pools of 100-150 strains against activity-enriched and unbiased compound libraries, probing more than 8.5 million chemical-genetic interactions. Primary screens identified over tenfold more hits than screening wild-type Mtb alone, with chemical-genetic interactions providing immediate, direct target insights. We identified over 40 compounds that target DNA gyrase, the cell wall, tryptophan, folate biosynthesis and RNA polymerase, as well as inhibitors that target EfpA. Chemical optimization yielded EfpA inhibitors with potent wild-type activity, thus demonstrating the ability of PROSPECT to yield inhibitors against targets that would have eluded conventional drug discovery.


Assuntos
Antituberculosos/classificação , Antituberculosos/isolamento & purificação , Descoberta de Drogas/métodos , Deleção de Genes , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Antituberculosos/farmacologia , DNA Girase/metabolismo , Resistência Microbiana a Medicamentos , Ácido Fólico/biossíntese , Terapia de Alvo Molecular , Mycobacterium tuberculosis/citologia , Mycobacterium tuberculosis/enzimologia , Ácidos Micólicos/metabolismo , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/classificação , Bibliotecas de Moléculas Pequenas/isolamento & purificação , Especificidade por Substrato , Inibidores da Topoisomerase II/isolamento & purificação , Inibidores da Topoisomerase II/farmacologia , Triptofano/biossíntese , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
4.
J Pak Med Assoc ; 69(1): 4-10, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30623904

RESUMO

OBJECTIVE: To determine the treatment outcomes of the drug-resistant tuberculosis patients who were previously exposed to second line drugs. METHODS: The retrospective study was conducted at eight Programmatic Management of Drug Resistant Tuberculosis (PMDT) sites in Sindh and Balochistan. Data of patients who were previously exposed to second line drugs and re-enrolled in the drug-resistant tuberculosis register at PMDT sites in Sindh and Balochistan between 2008 and 2016 was included for analysis. Data of those still under treatment or transferred to another treatment site was excluded. Association was explored between treatment outcomes and other independent variables, while in order to identify the risk factors associated with poor treatment outcomes univariate and multivariate logistic regression was used. RESULTS: Overall, there were 3645 patients and 288(8%) were previously exposed to second line drugs. Of them, 95(33%) were excluded, and the final sample stood at 193; 99(51.3%) males and 94(48.7%) females. The median age of the sample was 29 years (inter-quartile range: 22-41 years). The mean duration of treatment was 20}11.14 months. Overall success rate of the re-treatment of previously treated patients was 105(54.4%). Observed relapse rate was 9(4.7%).. CONCLUSIONS: The success rate for re-treatment drug-resistant tuberculosis patients was found to be unacceptably low. New drugs and novel regimens should be made widely available.


Assuntos
Antituberculosos , Mycobacterium tuberculosis , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Antituberculosos/classificação , Antituberculosos/uso terapêutico , Feminino , Humanos , Masculino , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Paquistão/epidemiologia , Retratamento/métodos , Retratamento/estatística & dados numéricos , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
7.
BMJ Open ; 8(9): e023899, 2018 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-30287613

RESUMO

INTRODUCTION: Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB. METHODS AND ANALYSIS: Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960. ETHICS AND DISSEMINATION: This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02816931; Pre-results.


Assuntos
Antituberculosos , Monitoramento de Medicamentos/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Antituberculosos/administração & dosagem , Antituberculosos/classificação , Antituberculosos/farmacocinética , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana/métodos , Mycobacterium tuberculosis/isolamento & purificação , Estudos Prospectivos , Teste Bactericida do Soro , Tuberculose Resistente a Múltiplos Medicamentos/sangue , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
9.
Respirology ; 23(11): 978-990, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29917287

RESUMO

Since standardized rifampin-based first-line regimens and fluoroquinolone-based second-line regimens were used to treat tuberculosis (TB), unfortunately without timely modification according to the drug resistance profile, TB and drug-resistant disease are still important public health threats worldwide. Although the last decade has witnessed advances in rapid diagnostic tools and use of repurposed and novel drugs for better managing drug-resistant TB, we need an appropriate TB control strategy and a well-functioning health infrastructure to ensure optimal operational use of rapid tests, judicious use of effective treatment regimens that can be rapidly tailored according to the drug resistance profile and timely management of risk factors and co-morbidities that promote infection and its progression to disease. We searched the published literature to discuss (i) standardized versus individualized therapies, including the choice between a single one-size-fit-all regimen versus different options with different key drugs determined mainly by rapid drug susceptibility testing, (ii) alternative regimens for managing drug-susceptible TB, (iii) evidence for using the World Health Organization (WHO) longer and shorter regimens for multidrug-resistant TB and (iv) evidence for using repurposed and novel drugs. We hope an easily applicable combination of biomarkers that accurately predict individual treatment outcome will soon be available to ultimately guide individualized therapy.


Assuntos
Antituberculosos , Protocolos Clínicos/normas , Mycobacterium tuberculosis/efeitos dos fármacos , Administração dos Cuidados ao Paciente , Tuberculose Resistente a Múltiplos Medicamentos , Antituberculosos/classificação , Antituberculosos/farmacologia , Saúde Global , Humanos , Administração dos Cuidados ao Paciente/métodos , Administração dos Cuidados ao Paciente/organização & administração , Administração dos Cuidados ao Paciente/tendências , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
11.
J Bras Pneumol ; 44(2): 153-160, 2018 Apr.
Artigo em Português, Inglês | MEDLINE | ID: mdl-29791557

RESUMO

Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.


Assuntos
Antituberculosos/uso terapêutico , Reposicionamento de Medicamentos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Antituberculosos/classificação , Ensaios Clínicos como Assunto , Diarilquinolinas/uso terapêutico , Humanos , Nitroimidazóis/uso terapêutico , Oxazóis/uso terapêutico
12.
J. bras. pneumol ; 44(2): 153-160, Mar.-Apr. 2018. tab
Artigo em Inglês | LILACS | ID: biblio-893913

RESUMO

ABSTRACT Multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively) continue to represent a challenge for clinicians and public health authorities. Unfortunately, although there have been encouraging reports of higher success rates, the overall rate of favorable outcomes of M/XDR-TB treatment is only 54%, or much lower when the spectrum of drug resistance is beyond that of XDR-TB. Treating M/XDR-TB continues to be a difficult task, because of the high incidence of adverse events, the long duration of treatment, the high cost of the regimens used, and the drain on health care resources. Various trials and studies have recently been undertaken (some already published and others ongoing), all aimed at improving outcomes of M/XDR-TB treatment by changing the overall approach, shortening treatment duration, and developing a universal regimen. The objective of this review was to summarize what has been achieved to date, as far as new and repurposed drugs are concerned, with a special focus on delamanid, bedaquiline, pretomanid, clofazimine, carbapenems, and linezolid. After more than 40 years of neglect, greater attention has recently been paid to the need for new drugs to fight the "white plague", and promising results are being reported.


RESUMO A tuberculose multirresistente (TB-MDR, do inglês multidrug-resistant) e a extensivamente resistente (TB-XDR, do inglês extensively drug-resistant) continuam representando um desafio para os clínicos e as autoridades de saúde pública. Infelizmente, embora haja relatos encorajadores de taxas de sucesso maiores, a taxa global de desfechos favoráveis do tratamento da TB-MDR/XDR é de apenas 54%, ou muito menor quando o espectro de resistência aos fármacos vai além do da TB-XDR. O tratamento da TB-MDR/XDR continua sendo uma tarefa difícil, em razão da alta incidência de eventos adversos, do longo tempo de tratamento, do alto culto dos esquemas utilizados e da drenagem dos recursos de saúde. Diversos ensaios e estudos foram realizados recentemente (alguns já publicados e outros em andamento), todos visando a melhorar os desfechos do tratamento da TB-MDR/XDR por meio da alteração da abordagem geral, redução do tempo de tratamento e desenvolvimento de um esquema universal. O objetivo desta revisão foi resumir o que se conseguiu até o momento, no que se refere a novos fármacos e fármacos repropostos, dando foco especial para delamanid, bedaquilina, pretomanida, clofazimina, carbapenêmicos e linezolida. Após mais de 40 anos de negligência, recentemente foi dada mais atenção á necessidade de novos fármacos para se combater a "praga branca", e resultados promissores estão sendo relatados.


Assuntos
Humanos , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Reposicionamento de Medicamentos , Antituberculosos/uso terapêutico , Oxazóis/uso terapêutico , Ensaios Clínicos como Assunto , Diarilquinolinas/uso terapêutico , Nitroimidazóis/uso terapêutico , Antituberculosos/classificação
14.
J Epidemiol Glob Health ; 8(3-4): 220-224, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30864767

RESUMO

Rapid detection of drug resistance in Mycobacterium tuberculosis is important for the successful treatment of tuberculosis. Fluoroquinolone and aminoglycoside resistance detection by molecular methods becomes more complex due to cross resistance among them. Thus, we aimed to determine cross-resistance and mutations in resistance genes for these drugs. A total of 336 multidrug-resistant tuberculosis (MDR-TB) cases received in Mycobacteriology laboratory were screened for phenotypic drug sensitivity testing for second-line drugs, i.e., ofloxacin, amikacin, kanamycin, and capreomycin. Molecular characterization of resistance was done by DNA sequencing of gyrA gene for fluoroquinolones (FQ), and multiplex allele-specific polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (RFLP) of rrs gene for aminoglycosides. Of 336 MDR-TB isolates, 12 were extensively drug-resistant tuberculosis and 219 were sensitive to all the drugs tested. Ofloxacin, amikacin, kanamycin, and capreomycin resistance was detected in 101 (30.1%), 23 (6.8%), 27 (8.1%), and 19 (5.6%) cases, respectively. Eight different mutations were detected in gyrA gene in ofloxacin-resistant isolates and A1401G nucleotide change in rrs gene were seen in 55.6% (15/27), 65.2% (15/23), and 68.4% (13/29) for kanamycin-, amikacin-, and capreomycin-resistant isolates, respectively. Information on second-line drug resistance-associated mutations could potentially be used for development of newer rapid diagnostic tests.


Assuntos
Antituberculosos , Farmacorresistência Bacteriana Múltipla/genética , Tuberculose Extensivamente Resistente a Medicamentos , Mycobacterium tuberculosis , Antituberculosos/classificação , Antituberculosos/uso terapêutico , Proteínas de Bactérias/genética , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Humanos , Índia/epidemiologia , Testes de Sensibilidade Microbiana/métodos , Mutação , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Mycobacterium tuberculosis/patogenicidade
15.
J Microbiol Immunol Infect ; 51(1): 88-93, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28698044

RESUMO

BACKGROUND: Multidrug-resistant and extensively drug-resistant tuberculosis infections cause public health concerns worldwide. Local epidemiologic data about the drug resistance of Mycobacterium tuberculosis isolate (Mtb) is critical to guide appropriate empirical therapy to cure patients and restrain the spread of tuberculosis. METHODS: Antituberculosis susceptibility testing was performed for 287 Mtbs, including 63 MDR-Mtbs collected in southern Taiwan from 2011 to 2015. Tuberculosis patients were classified into newly diagnosed cases and previously treated cases based on patients' medical history. RESULTS: Almost no resistance was found to the tested second-line antituberculosis drugs in non-MDR-Mtbs. Higher resistance rates to ethambutol, ofloxacin, and streptomycin were observed in MDR-Mtbs compared to non-MDR-Mtbs. Among 63 MDR-Mtbs, 61.9% of patients were newly diagnosed and 38.1% were previously treated cases. For MDR-Mtb, the drug-resistance rates in previously treated cases were significantly higher for ethambutol, pyrazinamide, ofloxacin, moxifloxacin, streptomycin, and p-aminosalicylic acid. When MDR-Mtbs are identified in previously treated cases, empirical administration of ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment. The resistance rates to these drugs were all more than 50%. Furthermore, 25% of MDR-Mtbs from previously treated patients were resistant to p-aminosalicylic acid. CONCLUSION: We observed almost no resistance to the tested second-line antituberculosis drugs among non-MDR-Mtbs. Anti-tuberculosis regimen with pyrazinamide, ethambutol, fluoroquinolone, kanamycin, cycloserine and p-aminosalicylic acid can be empirically used for newly diagnosed MDR-TB cases. For previously treated MDR-TB patients, empirical ethambutol, pyrazinamide, ofloxacin, or moxifloxacin may not provide effective treatment because the resistance rates to these drugs were all >50%.


Assuntos
Antituberculosos/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/epidemiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Ácido Aminossalicílico/uso terapêutico , Antituberculosos/classificação , Etambutol/uso terapêutico , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Fluoroquinolonas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina , Ofloxacino/uso terapêutico , Pirazinamida/uso terapêutico , Estreptomicina/uso terapêutico , Taiwan/epidemiologia
16.
Adv Exp Med Biol ; 1019: 221-246, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29116638

RESUMO

Drug Resistant Tuberculosis (DRTB) is an emerging problem world-wide. In order to control the disease and decrease the number of cases overtime a prompt diagnosis followed by an appropriate treatment should be provided to patients. Phenotypic DST based on liquid automated culture has greatly reduced the time needed to generate reliable data but has the drawback to be expensive and prone to contamination in the absence of appropriate infrastructures. In the past 10 years molecular biology tools have been developed. Those tools target the main mutations responsible for DRTB and are now globally accessible in term of cost and infrastructures needed for the implementation. The dissemination of the Xpert MTB/rif has radically increased the capacity to perform the detection of rifampicin resistant TB cases. One of the main challenges for the large scale implementation of molecular based tests is the emergence of conflicting results between phenotypic and genotypic tests. This mines the confidence of clinicians in the molecular tests and delays the initiation of an appropriate treatment. A new technique is revolutionizing the genotypic approach to DST: the WGS by Next-Generation Sequencing technologies. This methodology promises to become the solution for a rapid access to universal DST, able indeed to overcome the limitations of the current phenotypic and genotypic assays. Today the use of the generated information is still challenging in decentralized facilities due to the lack of automation for sample processing and standardization in the analysis.The growing knowledge of the molecular mechanisms at the basis of drug resistance and the introduction of high-performing user-friendly tools at peripheral level should allow the very much needed accurate diagnosis of DRTB in the near future.


Assuntos
Antituberculosos/uso terapêutico , Genes Bacterianos , Testes de Sensibilidade Microbiana/normas , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/tratamento farmacológico , Antituberculosos/classificação , Farmacorresistência Bacteriana Múltipla/genética , Evolução Molecular , Humanos , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Fenótipo , Rifampina/uso terapêutico , Escarro/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/transmissão , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/transmissão , Sequenciamento Completo do Genoma
17.
Arch Bronconeumol ; 53(9): 501-509, 2017 Sep.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28359606

RESUMO

In the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. Nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, from those infected by strains that are sensitive to all drugs, to those who are extensively drug-resistant. Specific recommendations are given forall cases. The current and future role of new molecular methods for detecting resistance, shorter multi-drug-resistant tuberculosis regimens, and new drugs with activity against Mycobacterium tuberculosis are also addressed.


Assuntos
Antituberculosos/uso terapêutico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/classificação , Antituberculosos/farmacologia , Busca de Comunicante , Gerenciamento Clínico , Quimioterapia Combinada , Tuberculose Extensivamente Resistente a Medicamentos/diagnóstico , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Técnicas de Genotipagem , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Guias de Prática Clínica como Assunto , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
18.
Trends Pharmacol Sci ; 38(4): 393-405, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28169001

RESUMO

Once considered a crowning achievement of modern drug development, tuberculosis (TB) chemotherapy has proven increasingly unable to keep pace with the spread of the pandemic and rise of drug resistance. Efforts to revive the TB drug development pipeline have, in the meantime, faltered. Closer analysis reveals key experimental deficiencies that have hindered our ability to 'reverse engineer' knowledge of antibiotic mechanisms into rational drug development. Here, we discuss the emerging potential of metabolomics; the systems level study of small molecule metabolites, to help overcome these gaps and serve as a unique biochemical bridge between the phenotypic properties of chemical compounds and biological targets.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas , Metabolômica , Antituberculosos/classificação , Resistência Microbiana a Medicamentos , Humanos
19.
Microbiol Spectr ; 5(1)2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28233509

RESUMO

While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in clinical settings. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of posttreatment relapse. Some promising drugs to treat tuberculosis, such as rifampin and bedaquiline, only kill nonreplicating M. tuberculosisin vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high-throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores.


Assuntos
Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , Tolerância a Medicamentos , Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Antituberculosos/química , Antituberculosos/classificação , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala
20.
Int J Infect Dis ; 56: 181-184, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27818361

RESUMO

The classification of anti-tuberculosis (TB) drugs is important as it helps the clinician to build an appropriate anti-TB regimen for multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB cases that do not fulfil the criteria for the shorter MDR-TB regimen. The World Health Organization (WHO) has recently approved a revision of the classification of new anti-TB drugs based on current evidence on each drug. In the previous WHO guidelines, the choice of drugs was based on efficacy and toxicity in a step-down manner, from group 1 first-line drugs and groups 2-5 second-line drugs, to group 5 drugs with potentially limited efficacy or limited clinical evidence. In the revised WHO classification, exclusively aimed at managing drug-resistant cases, medicines are again listed in hierarchical order from group A to group D. In parallel, a possible future classification is independently proposed. The aim of this viewpoint article is to describe the evolution in WHO TB classification (taking into account an independently proposed new classification) and recent changes in WHO guidance, while commenting on the differences between them. The latest evidence on the ex-group 5 drugs is also discussed.


Assuntos
Antituberculosos/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/uso terapêutico , Evolução Biológica , Monitoramento de Medicamentos , Humanos , Testes de Sensibilidade Microbiana , Organização Mundial da Saúde
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