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1.
BMJ ; 367: l5894, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649017

RESUMO

OBJECTIVE: To measure the association between phenotypic drug resistance and the risk of tuberculosis infection and disease among household contacts of patients with pulmonary tuberculosis. SETTING: 106 district health centers in Lima, Peru between September 2009 and September 2012. DESIGN: Prospective cohort study. PARTICIPANTS: 10 160 household contacts of 3339 index patients with tuberculosis were classified on the basis of the drug resistance profile of the patient: 6189 were exposed to drug susceptible strains of Mycobacterium tuberculosis, 1659 to strains resistant to isoniazid or rifampicin, and 1541 to strains that were multidrug resistant (resistant to isoniazid and rifampicin). MAIN OUTCOME MEASURES: Tuberculosis infection (positive tuberculin skin test) and the incidence of active disease (diagnosed by positive sputum smear or chest radiograph) after 12 months of follow-up. RESULTS: Household contacts exposed to patients with multidrug resistant tuberculosis had an 8% (95% confidence interval 4% to 13%) higher risk of infection by the end of follow-up compared with household contacts of patients with drug sensitive tuberculosis. The relative hazard of incident tuberculosis disease did not differ among household contacts exposed to multidrug resistant tuberculosis and those exposed to drug sensitive tuberculosis (adjusted hazard ratio 1.28, 95% confidence interval 0.9 to 1.83). CONCLUSION: Household contacts of patients with multidrug resistant tuberculosis were at higher risk of tuberculosis infection than contacts exposed to drug sensitive tuberculosis. The risk of developing tuberculosis disease did not differ among contacts in both groups. The evidence invites guideline producers to take action by targeting drug resistant and drug sensitive tuberculosis, such as early detection and effective treatment of infection and disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT00676754.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos/transmissão , Tuberculose Pulmonar/transmissão , Adolescente , Adulto , Idoso , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Criança , Pré-Escolar , Busca de Comunicante/métodos , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Estimativa de Kaplan-Meier , Masculino , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Peru/epidemiologia , Estudos Prospectivos , Rifampina/farmacologia , Rifampina/uso terapêutico , Escarro/microbiologia , Teste Tuberculínico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/epidemiologia , Tuberculose Pulmonar/microbiologia , Adulto Jovem
2.
Pan Afr Med J ; 33: 111, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31489089

RESUMO

Introduction: High mortality among individuals receiving retreatment for tuberculosis (RT-TB) persists, although reasons for these poor outcomes remain unclear. Methods: We retrospectively reviewed 394 RT-TB patients diagnosed between January 2010 and June 2016 in Accra, Ghana. Results: Of RT-TB patients, 161 (40.9%) were treated empirically (negative/absent smear, culture or Xpert), of whom 30.4% (49/161) had only extrapulmonary TB signs or symptoms. Mortality during treatment was 19.4%; 15-day mortality was 10.8%. In multivariable proportional hazards regression, living with HIV (aHR=2.69 [95 CI: 1.51, 4.80], p<0.01) and previous loss-to-follow up (aHR=8.27 (95 CI: 1.10, 62.25), p=0.04) were associated with mortality, while drug susceptibility testing (DST, aHR=0.36 (95 CI: 0.13, 1.01), p=0.052) was protective. Isoniazid resistance was observed in 40% (23/58 tested) and rifampin resistance in 19.1% (12/63 tested). Conclusion: High rates of extrapulmonary TB and smear/culture negative disease highlight the barriers to achieving DST-driven RT-TB regimens and the need for improved diagnostics. Our finding of poly-drug resistance in rifampin-susceptible cases supports access to comprehensive first line DST. Additionally, interventions to reduce mortality, especially in HIV co-infected RT-TB patients, are urgently needed.


Assuntos
Antituberculosos/administração & dosagem , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose/tratamento farmacológico , Adulto , Antituberculosos/farmacologia , Estudos de Coortes , Farmacorresistência Bacteriana Múltipla , Feminino , Gana , Infecções por HIV/epidemiologia , Humanos , Isoniazida/farmacologia , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Retratamento , Estudos Retrospectivos , Rifampina/farmacologia , Tuberculose/microbiologia , Tuberculose/mortalidade , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/mortalidade
3.
Chem Commun (Camb) ; 55(69): 10214-10217, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380528

RESUMO

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.


Assuntos
Azóis/química , Azóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cisteína/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
4.
Eur J Med Chem ; 181: 111578, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401536

RESUMO

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 µM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 µM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 µM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Carbamatos/química , Carbamatos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Carbamatos/síntese química , Células Hep G2 , Humanos , Isocitrato Liase/antagonistas & inibidores , Isocitrato Liase/metabolismo , Mycobacterium tuberculosis/enzimologia , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia , Salicilanilidas/síntese química , Salicilanilidas/química , Salicilanilidas/farmacologia , Tuberculose/tratamento farmacológico
5.
Eur J Med Chem ; 181: 111595, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408806

RESUMO

A series of benzothiazinones (BTZs) containing an oxime moiety, based on the structure of ZR-10 discovered in our lab, were designed and synthesized. Most of the compounds with alkoxyimino groups attached to the piperazine or cyclohexyl ring of PBTZ169, exhibit excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016-0.037 µg/mL) and low cell cytotoxicity. Two close PBTZ169-analogues 3a and 3b with proper ADME/T and PK properties show potent in vivo efficacy in an acute mouse model of tuberculosis. Compound 3a is under evaluation as a potential clinical candidate for treatment of tuberculosis.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oximas/farmacologia , Tiazinas/farmacologia , Animais , Antituberculosos/química , Antituberculosos/farmacocinética , Desenho de Drogas , Feminino , Humanos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Oximas/química , Oximas/farmacocinética , Piperazinas , Tiazinas/química , Tiazinas/farmacocinética , Tuberculose/tratamento farmacológico
6.
Mikrobiyol Bul ; 53(3): 245-253, 2019 Jul.
Artigo em Turco | MEDLINE | ID: mdl-31414626

RESUMO

Tuberculosis (TB) is a chronic, granulomatous and necrotizing disease caused by microorganisms belonging to the Mycobacterium tuberculosis complex group. In 2017, 6.4 million new TB cases have been reported according to the World Health Organization 2018 Global Tuberculosis Report. TB remains among the major health problems of our time due to the increasing drug resistance problem and the difficulties in definitive diagnosis in recent years. It is stated by clinicians that intensive use of quinolone group drugs with oral form in simple indications such as respiratory or urinary tract infections may lead to resistance and this may result in treatment failures. The aim of this study was to determine the moxifloxacin susceptibility of M.tuberculosis isolates obtained from clinical specimens by phenotypical methods, to determine the resistance rates of moxifloxacin and to investigate the relationship between phenotypical resistance and mutations in the gyrA gene. A hundred (n= 100) consecutive non-multidrug resistant and 37 non-consecutive multidrug resistant M.tuberculosis strains isolated from the clinical specimens of patients with pulmonary tuberculosis were included in the study. The moxifloxacin susceptibility of the isolates was determined by using Löwenstein-Jensen medium and their epidemiological properties were investigated and also mutations detected by gyrA region were compared with drug susceptibility rates. Of the 137 isolates tested for phenotypical susceptibility, 25 (18.2%) were found to be resistant to moxifloxacin. Resistance rate among non-multidrug resistant and multidrug resistant isolates were determined as 17% and 21.6%, respectively. According to the results of the sequencing analysis, of the gyrA regions of all the isolates included in the study, a single base mutation was found in a total of six samples. The location positions of the mutations were determined as D94Y, D94G, A90V, G88A and among two strains as D89N. Two of the isolates with mutations were found to be phenotypically susceptible to moxifloxacin. In our study, it was found that moxifloxacin resistance in M.tuberculosis isolates was higher than similar studies and it was found that different mechanisms may be responsible for the existing resistance other than the mutations in the gyrA gene. It was concluded that the data obtained from the study should be shared with all clinicians in the country due to the possibility of resistance development to this group of drugs in a short time and considering this drug will have an important role in the treatment of TB, it should be used more limited in non-specific indications. Further studies using larger case groups and isolates are needed for the continuation of the research.


Assuntos
Farmacorresistência Bacteriana , Moxifloxacina , Mycobacterium tuberculosis , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/genética , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Mutação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética
7.
Tuberk Toraks ; 67(2): 92-101, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31414639

RESUMO

Introduction: Tuberculosis (TB) is continuing to be a important public health problem in the undeveloped countries. Drug sensitivity rate should be monitored for the effective treatment and control in the TB. The aim of this study was to determine the rate of resistance to first line TB drugs in the Mycobacterium tuberculosis complex isolates. Materials and Methods: During one-year period, M. tuberculosis complex was isolated in the 1193 samples from 974 patients in the Mycobacterial Laboratory of Yedikule Chest Diseases and Chest Surgery Education and Research Hospital, Istanbul, Turkey. The majority of samples isolated in the M. tuberculosis complex were sputum (n= 897, 92.1%). Anti-TB drug susceptibility testing was performed with Mycobacterium Growth Indicator Tube 960 system. Result: Two hundred and sixty isolat (26.7%) were resistant to at least one of the four first-line anti-TB drugs tested. One hundred ninety seven isolates were resistances to isoniazid (20.2%); 82 to rifampin (8.4%), 63 to ethambutol (6.5%) and 140 to streptomycin (14.4%). Of the 197 isoniazid-resistant isolates, 89 (45.2%) isolates was only isoniazid-resistance, only rifampin-resistance were found 15.9% (n= 13), ethambutol 7.9% (n= 5) and streptomycin 30.7% (n= 43). There were 48 (4.9%) isolates with two drugresistance, 22 (2.3%) isolates with three drug-resistance, and 42 (4.3%) isolates with four drug-resistance. The multidrug resistance rate was 7% (68 of 974). There was no relationship with between the frequency of TB drug resistance and gender or age. The isoniazid--resistance and streptomycin-resistance were seen to tend to increase if together considered the results of this study with outcomes of previously reported studies from Turkey in the 1998-2003, 2004-2007 and 2008-2010 years. Conclusions: Monitoring of drug susceptibility test results can contribute to the management of TB treatment and increase treatment success. Isoniazid-resistance and streptomycin-resistance tend to increase in Turkey. Further clinical studies are needed to investigate regional and global factors affecting the development of resistance to first-line TB drugs.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Antituberculosos/uso terapêutico , Etambutol/farmacologia , Etambutol/uso terapêutico , Feminino , Humanos , Isoniazida/farmacologia , Isoniazida/uso terapêutico , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Saúde Pública , Rifampina/farmacologia , Rifampina/uso terapêutico , Escarro/microbiologia , Estreptomicina/farmacologia , Estreptomicina/uso terapêutico , Centros de Atenção Terciária , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Turquia , Adulto Jovem
9.
Pan Afr Med J ; 32: 196, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31312308

RESUMO

Multidrug-resistant tuberculosis is a major challenge for the World Health Organization. Its growing incidence and the diagnostic and therapeutic difficulties make it a public health problem especially in the developing countries. We report two cases of extrapulmonary drug-resistant tuberculosis (nodal and osteo-articular) and five cases of pulmonary tuberculosis and extra-pulmonary tuberculosis (pleural, nodal, anal and neuro-meningeal) in hospitalized patients at the Hopital Moulay Youssef in Rabat. This study reports the issue of drug-resistant TB and highlights the role of genotypic tests in the diagnosis of extrapulmonary tuberculosis.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Tuberculose Pulmonar/epidemiologia , Adulto , Antituberculosos/administração & dosagem , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/tratamento farmacológico
10.
Biochemistry (Mosc) ; 84(5): 540-552, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31234768

RESUMO

L-Arabinose is an important component of mycobacterial cell wall. L-Arabinose is involved in the synthesis of arabinogalactan, lipoarabinomannan, and other sugar compounds, which suggests that it can modulate cell wall permeability and drug resistance. However, whether L-arabinose affects mycobacterial antibiotic resistance and the underlying regulatory mechanism remains unclear. In this study, we characterized a new transcription factor of Mycobacterium smegmatis, AraR, that responds to L-arabinose and regulates mycobacterial sensitivity to isoniazid (INH). AraR specifically recognizes two conserved 15-bp motifs within the upstream regulatory region of the arabinose (araR) operon. AraR functions as a transcriptional repressor that negatively regulates araR expression. In contrast to the effect of AraR, overexpression of the araR operon contributes to the mycobacterial INH resistance. L-arabinose acts as an effector and derepresses transcriptional inhibition by AraR. The araR-deficient strain is more resistant to INH than the wild-type strain, whereas the araR-overexpressing strain is more sensitive to INH. Addition of L-arabinose to the medium can significantly increase the resistance to INH of the wild-type strain, but not of the araR knockout strain. Therefore, we identified a new L-arabinose-responding transcription factor and revealed its effect on the bacterial antibiotic resistance. These findings can provide new insights in the regulatory mechanisms mediated by sugar molecules and their relationship with drug resistance in mycobacteria.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Isoniazida/farmacologia , Mycobacterium smegmatis/metabolismo , Fatores de Transcrição/metabolismo , Arabinose/química , Arabinose/metabolismo , Proteínas de Bactérias/genética , Sequência de Bases , Mycobacterium smegmatis/efeitos dos fármacos , Óperon , Ligação Proteica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Fatores de Transcrição/genética
12.
Pan Afr Med J ; 32: 124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236189

RESUMO

Introduction: hain GenoType MTBDRsl is nucleic acid amplification assay based on reverse hybridization with specific oligonucleotide probes on nitrocellulose strips. MTBDRsl identifies M. tuberculosis complex and detects resistance to fluoroquinolone, second line injectable drugs and ethambutol evident as mutations of gyrA, rrs and embB genes respectively. This study aimed to evaluate the diagnostic performance of the Hain GenoType MTBDRsl Assay using 1% proportion method on LJ medium as gold standard. Methods: a total of 52 rifampicin resistant (RR) isolates were tested for second line drug sensitivity by 1% proportion method and by MTBDRsl assay. Results: two strains were identified as mycobacteria other than tuberculosis MOTT and the rest were Mycobacterium tuberculosis complex MTBC. Five of the MTBC isolates (5/50; 10%) showed resistance to at least one second line drug and one isolate (1/50; 2%) was XDR. XDR strain was concordantly detected by the two methods. One of two Kanamycin-resistant isolates showed discordant results. Ofloxacin showed one false positive and one false negative result. Most discrepancies were detected with Ethambutol. The sensitivity, specificity, positive and negative predictive values were respectively as follows: Ethambutol (63.3.4%, 85.7%, 94.4% and 62%), for Kanamycin (67%, 100%, 100% and 97.9%), for Amikacin and Capreomycin (100%, 100%, 100% and 100%), for Ofloxacin (75%, 97.5%, 75% and 97.8%). For XDR isolate the values were 100%, 100%, 100% and 100% respectively. Conclusion: MTBDRsl showed high specificity and negative predictive values making it acceptable and time-saving for early presumptive detection of resistance to second-line drugs in Sudan.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/isolamento & purificação , Técnicas de Amplificação de Ácido Nucleico , Tuberculose/diagnóstico , Farmacorresistência Bacteriana Múltipla , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Sudão , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
13.
Eur J Med Chem ; 178: 715-725, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229874

RESUMO

A series of N-(2-phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides (IPAs), based on the structure of WZY02 discovered in our lab, were designed and synthesized as new anti-TB agents. Results reveal that many of them exhibit excellent in vitro inhibitory activity with low nanomolar MIC values against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates. Compounds 15b and 15d display good safety and pharmacokinetic profiles, suggesting their promising potential to be lead compounds for future antitubercular drug discovery.


Assuntos
Antituberculosos/farmacologia , Desenho de Drogas , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piridinas/farmacologia , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Relação Dose-Resposta a Droga , Feminino , Imidazóis/administração & dosagem , Imidazóis/química , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/administração & dosagem , Piridinas/química , Relação Estrutura-Atividade
14.
Protein Pept Lett ; 26(9): 648-663, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31218945

RESUMO

After decades of efforts, tuberculosis has been well controlled in most places. The existing drugs are no longer sufficient for the treatment of drug-resistant Mycobacterium tuberculosis due to significant toxicity and selective pressure, especially for XDR-TB. In order to accelerate the development of high-efficiency, low-toxic antituberculosis drugs, it is particularly important to use Computer Aided Drug Design (CADD) for rational drug design. Here, we systematically reviewed the specific role of molecular simulation in the discovery of new antituberculosis drugs. The purpose of this review is to overview current applications of molecular simulation methods in the discovery of antituberculosis drugs. Furthermore, the unique advantages of molecular simulation was discussed in revealing the mechanism of drug resistance. The comprehensive use of different molecular simulation methods will help reveal the mechanism of drug resistance and improve the efficiency of rational drug design. With the help of molecular simulation methods such as QM/MM method, the mechanisms of biochemical reactions catalyzed by enzymes at atomic level in Mycobacterium tuberculosis has been deeply analyzed. QSAR and virtual screening both accelerate the development of highefficiency, low-toxic potential antituberculosis drugs. Improving the accuracy of existing algorithms and developing more efficient new methods for CADD will always be a hot topic in the future. It is of great value to utilize molecular dynamics simulation to investigate complex systems that cannot be studied in experiments, especially for drug resistance of Mycobacterium tuberculosis.


Assuntos
Antituberculosos/química , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Algoritmos , Antituberculosos/farmacologia , Projeto Auxiliado por Computador , Teoria da Densidade Funcional , Desenho de Drogas , Farmacorresistência Bacteriana , Humanos , Relação Quantitativa Estrutura-Atividade
15.
Eur J Med Chem ; 179: 208-217, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254922

RESUMO

IMB1603, a new benzothiazinone lead discovered by our lab, exhibited potent anti-MTB activity in vitro and in vivo, but significant hERG binding potency (IR > 90% at 10 µM). Thus, we embarked on a lead optimization program with the goal of identifying alternative leads that could reduce the hERG liability without sacrificing antimycobacterial potency. Compounds 2c and 4c were identified to maintain the anti-MTB activity (MICs <0.035-0.078 µM), and had lower hERG binding affinity (IR < 50% at 10 µM). Both of them were also found to have acceptable safety and pharmacokinetic properties. Studies to determine the in vivo efficacy of 2c and 4c are currently underway.


Assuntos
Antituberculosos/farmacologia , Benzotiazóis/farmacologia , Descoberta de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/síntese química , Antituberculosos/química , Benzotiazóis/síntese química , Benzotiazóis/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade
16.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31172969

RESUMO

The incidence of tuberculosis (TB) in some countries increases continuously, especially caused by mycobacterial strains resistant to various anti-tuberculotic drugs (AT). The emergence and spread of drug-resistant tuberculosis (multidrug-resistant - MDR-TB, and extensively drug-resistant - XDR-TB) suggest the crucial role of pharmacotherapy protocol tailored to the respective patient with MDR-TB or XDR-TB (a personalized approach) and requirements for fast and precise diagnostics of the degree of resistance. The aim of this study was to characterize a molecular basis of resistance to AT, and to identify the presence of the resistance using conventional susceptibility testing and molecular genetic methods using PCR tests in Slovakia during years 2009 - 2017. Furthermore, we focused on evaluation of the relationship between the level of resistance, the clinical status, and some laboratory markers of patients with drug-resistant TB. Totally 1157 strains isolated from patients in 2009 - 2017 were tested for resistance using classical methods and in resistant strains, the molecular-genetic tests were performed. Increased incidence of recurrence, prolonged time required to culture conversion, increased mortality during treatment, plasma C-reactive protein concentrations and sedimentation rate, broader spectrum of AT used, as well as higher incidence of adverse effects (sufficiently controlled with symptomatic treatment) were observed with higher degree of resistance. Contrary, the number of patients who achieved remission decreased. Rapid and precise identification of MDR-TB or XDR-TB strains using both classical and molecular-genetic testing is an essential tool for personalized drug treatment and prevention of resistance spread and worsening. Both tests should be used for correct diagnosis of resistant TB. Higher level of resistance required more aggressive therapeutic approach, associated with adverse effects and prolongation of the culture conversion time, as well as increased risk of relapse. Effective pharmacotherapy led to significant decrease of CRP levels in all groups of patients. The most frequent adverse effects of ATs - impairment of liver and kidney functions - were effectively managed by symptomatic treatment.


Assuntos
Farmacorresistência Bacteriana Múltipla/genética , Mycobacterium tuberculosis/genética , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Adulto , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , DNA Bacteriano/análise , Humanos , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Fenótipo , Eslováquia/epidemiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia
17.
Eur J Med Chem ; 178: 39-47, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176094

RESUMO

Tuberculosis (TB) has recently become the leading killer among infectious diseases. Multidrug and extensively drug-resistant Mycobacterium tuberculosis strains urge the need to develop anti-TB drugs with a novel mechanism of action. We describe synthesis of 22 novel imidazo[1,2-b][1,2,4,5]tetrazine derivatives with different substituents at C(3) and C(6) positions, and their antimycobacterial activity in vitro. 8 compounds show activity as potential serine/threonine protein kinase (STPK) inhibitors in M. smegmatis aphVIII+ test-system, which is characteristic for this class. 3 compounds out of 5 most active STPK inhibitors have a prominent minimal inhibitory concentration on M. tuberculosis H37Rv of 1 µg/ml. We were able to obtain M. smegmatis mc2 155 mutants resistant to 4 compounds and show that they do not have cross resistance with other drugs, but have a common mechanism of resistance among these 4 imidazo[1,2-b][1,2,4,5]tetrazines. Compound 3h seems the most promising, combining a predicted STPK inhibitor activity, the lowest MIC on M. tuberculosis and a low frequency of drug resistant mutants' emergence.


Assuntos
Antituberculosos/farmacologia , Compostos Heterocíclicos com 2 Anéis/farmacologia , Imidazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Resistência Microbiana a Medicamentos/efeitos dos fármacos , Eritromicina/farmacologia , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Imidazóis/síntese química , Imidazóis/química , Imipenem/farmacologia , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/enzimologia , Mycobacterium tuberculosis/efeitos dos fármacos , Ofloxacino/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Rifampina/farmacologia
18.
Eur J Med Chem ; 178: 315-328, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31195172

RESUMO

The dormant and resistant form of Mycobacterium tuberculosis presents a challenge in developing new anti-tubercular drugs. Herein, we report the synthesis and evaluation of trisubstituted thiazoles as antituberculosis agents. The SAR study has identified a requirement of hydrophobic substituent at C2, ester functionality at C4, and various groups with hydrogen bond acceptor character at C5 of thiazole scaffold. This has led to the identification of 13h and 13p as lead compounds. These compounds inhibited the dormant Mycobacterium tuberculosis H37Ra strain and M. tuberculosis H37Rv selectively. Importantly, 13h and 13p were non-toxic to CHO cells. The 13p showed activity against multidrug-resistant tuberculosis isolates.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/farmacologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Antituberculosos/síntese química , Antituberculosos/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
19.
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
20.
J Med Microbiol ; 68(8): 1137-1139, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31210631

RESUMO

Bedaquiline (BDQ) is a recently approved antibiotic for the treatment of multidrug-resistant tuberculosis, but its potential against slow-growing mycobacteria (SGM) is still unknown. The objective of this study was to determine the in vitro activity of BDQ on SGM by assessing their MIC and minimal bactericidal concentration (MBC). The MIC of BDQ against 17 clinical isolates including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium kansasii and Mycobacterium simiae species was determined by the resazurin microtitre assay and the MBC by the c.f.u. determination on 7H10 agar plates. BDQ has a bacteriostatic activity on all SGM tested with a MIC range from 0.03 to 0.007 µg ml-1 and surprisingly a good bactericidal activity on the majority of the isolates tested with an MBC of 1-2 µg ml-1 . Based on these preliminary results BDQ seems to be very promising for treatment of diseases caused by SGM.


Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Humanos , Viabilidade Microbiana/efeitos dos fármacos , Infecções por Micobactéria não Tuberculosa/microbiologia , Micobactérias não Tuberculosas/crescimento & desenvolvimento
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