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1.
Cell ; 170(2): 249-259.e25, 2017 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-28669536

RESUMO

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.


Assuntos
Antituberculosos/farmacologia , Benzofuranos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/farmacologia , Tuberculose/microbiologia , Animais , Antituberculosos/química , Benzofuranos/química , Benzofuranos/farmacocinética , Linhagem Celular , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Piperidinas/química , Piperidinas/farmacocinética , Organismos Livres de Patógenos Específicos
2.
Antimicrob Agents Chemother ; 65(11): e0058321, 2021 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-34370580

RESUMO

Multiple drug discovery initiatives for tuberculosis are currently ongoing to identify and develop new potent drugs with novel targets in order to shorten treatment duration. One of the drug classes with a new mode of action is DprE1 inhibitors targeting an essential process in cell wall synthesis of Mycobacterium tuberculosis. In this investigation, three DprE1 inhibitors currently in clinical trials, TBA-7371, PBTZ169, and OPC-167832, were evaluated side-by-side as single agents in the C3HeB/FeJ mouse model presenting with caseous necrotic pulmonary lesions upon tuberculosis infection. The goal was to confirm the efficacy of the DprE1 inhibitors in a mouse tuberculosis model with advanced pulmonary pathology and perform comprehensive analysis of plasma, lung, and lesion-centric drug levels to establish pharmacokinetic-pharmacodynamic (PK-PD) parameters predicting efficacy at the site of infection. Results showed significant efficacy for all three DprE1 inhibitors in the C3HeB/FeJ mouse model after 2 months of treatment. Superior efficacy was observed for OPC-167832 even at low-dose levels, which can be attributed to its low MIC, favorable distribution, and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions, where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment.


Assuntos
Mycobacterium tuberculosis , Tiazinas , Tuberculose , Animais , Camundongos , Camundongos Endogâmicos C3H , Piperazinas , Tuberculose/tratamento farmacológico
3.
Antimicrob Agents Chemother ; 60(10): 6271-80, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27503647

RESUMO

The recent development and spread of extensively drug-resistant and totally drug-resistant resistant (TDR) strains of Mycobacterium tuberculosis highlight the need for new antitubercular drugs. Protein synthesis inhibitors have played an important role in the treatment of tuberculosis (TB) starting with the inclusion of streptomycin in the first combination therapies. Although parenteral aminoglycosides are a key component of therapy for multidrug-resistant TB, the oxazolidinone linezolid is the only orally available protein synthesis inhibitor that is effective against TB. Here, we show that small-molecule inhibitors of aminoacyl-tRNA synthetases (AARSs), which are known to be excellent antibacterial protein synthesis targets, are orally bioavailable and effective against M. tuberculosis in TB mouse infection models. We applied the oxaborole tRNA-trapping (OBORT) mechanism, which was first developed to target fungal cytoplasmic leucyl-tRNA synthetase (LeuRS), to M. tuberculosis LeuRS. X-ray crystallography was used to guide the design of LeuRS inhibitors that have good biochemical potency and excellent whole-cell activity against M. tuberculosis Importantly, their good oral bioavailability translates into in vivo efficacy in both the acute and chronic mouse models of TB with potency comparable to that of the frontline drug isoniazid.


Assuntos
Antituberculosos/farmacologia , Leucina-tRNA Ligase/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Administração Oral , Animais , Antituberculosos/administração & dosagem , Antituberculosos/química , Antituberculosos/farmacocinética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Leucina-tRNA Ligase/química , Leucina-tRNA Ligase/genética , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Mycobacterium smegmatis/efeitos dos fármacos , Mycobacterium smegmatis/genética , Mycobacterium tuberculosis/genética , Inibidores da Síntese de Proteínas/administração & dosagem , Inibidores da Síntese de Proteínas/química , Inibidores da Síntese de Proteínas/farmacocinética , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Células Vero
4.
Antimicrob Agents Chemother ; 56(7): 3957-9, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22547626

RESUMO

Here we describe an experimental murine model that allows for aerosolized antituberculosis drug efficacy testing. Intrapulmonary aerosol delivery of isoniazid, capreomycin, and amikacin to mice with pulmonary infection of Mycobacterium tuberculosis demonstrated efficacy in reducing pulmonary bacterial loads similar to that seen by standard drug delivery methods, even when lower concentrations of drugs and fewer doses were used in the aerosolized drug regimens. Interestingly, intrapulmonary delivery of isoniazid also reduced the bacterial load in the spleen.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Isoniazida/administração & dosagem , Isoniazida/uso terapêutico , Pulmão/metabolismo , Tuberculose Pulmonar/tratamento farmacológico , Administração por Inalação , Animais , Feminino , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade
5.
Antimicrob Agents Chemother ; 56(2): 731-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22143517

RESUMO

In preclinical testing of antituberculosis drugs, laboratory-adapted strains of Mycobacterium tuberculosis are usually used both for in vitro and in vivo studies. However, it is unknown whether the heterogeneity of M. tuberculosis stocks used by various laboratories can result in different outcomes in tests of antituberculosis drug regimens in animal infection models. In head-to-head studies, we investigated whether bactericidal efficacy results in BALB/c mice infected by inhalation with the laboratory-adapted strains H37Rv and Erdman differ from each other and from those obtained with clinical tuberculosis strains. Treatment of mice consisted of dual and triple drug combinations of isoniazid (H), rifampin (R), and pyrazinamide (Z). The results showed that not all strains gave the same in vivo efficacy results for the drug combinations tested. Moreover, the ranking of HRZ and RZ efficacy results was not the same for the two H37Rv strains evaluated. The magnitude of this strain difference also varied between experiments, emphasizing the risk of drawing firm conclusions for human trials based on single animal studies. The results also confirmed that the antagonism seen within the standard HRZ regimen by some investigators appears to be an M. tuberculosis strain-specific phenomenon. In conclusion, the specific identity of M. tuberculosis strain used was found to be an important variable that can change the apparent outcome of in vivo efficacy studies in mice. We highly recommend confirmation of efficacy results in late preclinical testing against a different M. tuberculosis strain than the one used in the initial mouse efficacy study, thereby increasing confidence to advance potent drug regimens to clinical trials.


Assuntos
Antituberculosos/uso terapêutico , Isoniazida/uso terapêutico , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Humanos , Isoniazida/farmacologia , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Mycobacterium tuberculosis/genética , Pirazinamida/administração & dosagem , Pirazinamida/farmacologia , Rifampina/administração & dosagem , Rifampina/farmacologia , Resultado do Tratamento , Tuberculose Pulmonar/microbiologia
6.
Antimicrob Agents Chemother ; 56(1): 28-35, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22037847

RESUMO

One of the most effective and widely used antituberculosis (anti-TB) drugs is isoniazid (INH), a prodrug activated via oxidation that forms an adduct with NAD(+) to inhibit NADH-dependent targets of Mycobacterium tuberculosis, such as enoyl-acyl carrier protein reductase (InhA). The metabolic by-products and potentially toxic intermediates resulting from INH therapy have been identified through a large body of work. However, an INH-NAD adduct or structures related to this adduct have not been identified in specimens from human TB patients or animal models of TB. Analyses by mass spectrometry of urine collected from TB patients in a study conducted by the NIAID-funded Tuberculosis Research Unit identified 4-isonicotinoylnicotinamide (C(12)H(9)N(3)O(2)) as a novel metabolite of INH therapy. This compound was formed by M. tuberculosis strains in a KatG-dependent manner but could also be produced by mice treated with INH independent of an M. tuberculosis infection. Thus, the 4-isonicotinoylnicotinamide observed in human urine samples is likely derived from the degradation of oxidized INH-NAD adducts and provides direct evidence of host INH activation.


Assuntos
Antituberculosos/urina , Isoniazida/análogos & derivados , Isoniazida/urina , Mycobacterium tuberculosis/efeitos dos fármacos , NAD/análogos & derivados , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/urina , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/metabolismo , Biotransformação , Catalase/metabolismo , Cromatografia Líquida , Farmacorresistência Bacteriana , Feminino , Humanos , Isoniazida/farmacologia , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/enzimologia , NAD/urina , Oxirredução , Oxirredutases/metabolismo , Tuberculose Pulmonar/microbiologia
7.
Antimicrob Agents Chemother ; 55(3): 1237-47, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21135176

RESUMO

Methodologies for preclinical animal model testing of drugs against Mycobacterium tuberculosis vary from laboratory to laboratory; however, it is unknown if these variations result in different outcomes. Thus, a series of head-to-head comparisons of drug regimens in three commonly used mouse models (intravenous, a low-dose aerosol, and a high-dose aerosol infection model) and in two strains of mice are reported here. Treatment with standard tuberculosis (TB) drugs resulted in similar efficacies in two mouse species after a low-dose aerosol infection. When comparing the three different infection models, the efficacies in mice of rifampin and pyrazinamide were similar when administered with either isoniazid or moxifloxacin. Relapse studies revealed that the standard drug regimen showed a significantly higher relapse rate than the moxifloxacin-containing regimen. In fact, 4 months of the moxifloxacin-containing combination regimen showed similar relapse rates as 6 months of the standard regimen. The intravenous model showed slower bactericidal killing kinetics with the combination regimens tested and a higher relapse of infection than either aerosol infection models. All three models showed similar outcomes for in vivo efficacy and relapse of infection for the drug combinations tested, regardless of the mouse infection model used. Efficacy data for the drug combinations used also showed similar results, regardless of the formulation used for rifampin or timing of the drugs administered in combination. In all three infection models, the dual combination of rifampin and pyrazinamide was less sterilizing than the standard three-drug regimen, and therefore the results do not support the previously reported antagonism between standard TB agents.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/patogenicidade , Tuberculose/tratamento farmacológico , Animais , Quimioterapia Combinada , Feminino , Isoniazida/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pirazinamida/uso terapêutico , Rifampina/uso terapêutico , Tuberculose/microbiologia
9.
PLoS One ; 15(1): e0227224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31905374

RESUMO

The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 µM and mono-drug resistant potency ranging from 0.0017 to 7 µM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng·hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.


Assuntos
Antituberculosos/uso terapêutico , Imidazóis/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tiazóis/uso terapêutico , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/química , Antituberculosos/farmacologia , Células CACO-2 , Chlorocebus aethiops , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/crescimento & desenvolvimento , Células RAW 264.7 , Tiazóis/química , Tiazóis/farmacologia , Células Vero
10.
Antimicrob Agents Chemother ; 53(1): 306-8, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18852269

RESUMO

This study describes an in vivo model for evaluating the sterilizing activity of compounds against persisting Mycobacterium tuberculosis. The initial treatment with isoniazid and rifampin in granulocyte-macrophage colony-stimulating factor gene-disrupted mice reduced the number of bacteria more than 99% within 3 weeks. A subsequent treatment with individual drugs was performed to assess their activity on the 1% of remaining bacilli and disease relapse.


Assuntos
Antituberculosos/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/genética , Animais , Bacillus/efeitos dos fármacos , Modelos Animais de Doenças , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Camundongos , Camundongos Mutantes , Baço/efeitos dos fármacos , Baço/microbiologia
11.
Bioorg Med Chem ; 17(10): 3588-94, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19386501

RESUMO

Direct anti-tuberculosis screening of commercially available compound libraries identified a novel piperidinol with interesting anti-tuberculosis activity and drug like characteristics. To generate a structure activity relationship about this hit a 22 member optimization library was generated using parallel synthesis. Products of this library 1-((R)-3-(4-chlorophenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl)piperidin-4-ol and 1-((S)-3-(4-(trifluoromethyl) phenoxy)-2-hydroxypropyl)-4-(4-chloro-3-(trifluoromethyl) phenyl) piperidin-4-ol demonstrated good anti-tuberculosis activity. Unfortunately, side effects were observed upon in vivo anti-tuberculosis testing of these compounds precluding their further advancement, which may be in part due to the secondary pharmacology associated with the aryl piperidinol core.


Assuntos
Antituberculosos/síntese química , Antituberculosos/toxicidade , Piperidinas/síntese química , Piperidinas/toxicidade , Animais , Antituberculosos/química , Chlorocebus aethiops , Descoberta de Drogas , Piperidinas/química , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade , Células Vero
12.
ACS Infect Dis ; 5(2): 239-249, 2019 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-30485737

RESUMO

Respiration is a promising target for the development of new antimycobacterial agents, with a growing number of compounds in clinical development entering this target space. However, more candidate inhibitors are needed to expand the therapeutic options available for drug-resistant Mycobacterium tuberculosis infection. Here, we characterize a putative respiratory complex III (QcrB) inhibitor, TB47: a pyrazolo[1,5- a]pyridine-3-carboxamide. TB47 is active (MIC between 0.016 and 0.500 µg/mL) against a panel of 56 M. tuberculosis clinical isolates, including 37 multi-drug-resistant and two extensively drug-resistant strains. Pharmacokinetic and toxicity studies showed promising profiles, including negligible CYP450 interactions, cytotoxicity, and hERG channel inhibition. Consistent with other reported QcrB inhibitors, TB47 inhibits oxygen consumption only when the alternative oxidase, cytochrome bd, is deleted. A point mutation in the qcrB cd2-loop (H190Y, M. smegmatis numbering) rescues the inhibitory effects of TB47. Metabolomic profiling of TB47-treated M. tuberculosis H37Rv cultures revealed accumulation of steps in the TCA cycle and pentose phosphate pathway that are linked to reducing equivalents, suggesting that TB47 causes metabolic redox stress. In mouse infection models, a TB47 monotherapy was not bactericidal. However, TB47 was strongly synergistic with pyrazinamide and rifampicin, suggesting a promising role in combination therapies. We propose that TB47 is an effective lead compound for the development of novel tuberculosis chemotherapies.


Assuntos
Antituberculosos/farmacologia , Complexo III da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/farmacocinética , Feminino , Metabolômica , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Piridinas/farmacologia
13.
Life Sci Alliance ; 1(3): e201800025, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30456352

RESUMO

New antitubercular agents are needed to combat the spread of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis. The frontline antitubercular drug isoniazid (INH) targets the mycobacterial enoyl-ACP reductase, InhA. Resistance to INH is predominantly through mutations affecting the prodrug-activating enzyme KatG. Here, we report the identification of the diazaborines as a new class of direct InhA inhibitors. The lead compound, AN12855, exhibited in vitro bactericidal activity against replicating bacteria and was active against several drug-resistant clinical isolates. Biophysical and structural investigations revealed that AN12855 binds to and inhibits the substrate-binding site of InhA in a cofactor-independent manner. AN12855 showed good drug exposure after i.v. and oral delivery, with 53% oral bioavailability. Delivered orally, AN12855 exhibited dose-dependent efficacy in both an acute and chronic murine model of tuberculosis infection that was comparable with INH. Combined, AN12855 is a promising candidate for the development of new antitubercular agents.

14.
PLoS One ; 9(2): e87909, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24505329

RESUMO

The reductively activated nitroaromatic class of antimicrobials, which include nitroimidazole and the more metabolically labile nitrofuran antitubercular agents, have demonstrated some potential for development as therapeutics against dormant TB bacilli. In previous studies, the pharmacokinetic properties of nitrofuranyl isoxazolines were improved by incorporation of the outer ring elements of the antitubercular nitroimidazole OPC-67683. This successfully increased stability of the resulting pentacyclic nitrofuran lead compound Lee1106 (referred to herein as 9a). In the current study, we report the synthesis and antimicrobial properties of 9a and panel of 9a analogs, which were developed to increase oral bioavailability. These hybrid nitrofurans remained potent inhibitors of Mycobacterium tuberculosis with favorable selectivity indices (>150) and a narrow spectrum of activity. In vivo, the pentacyclic nitrofuran compounds showed long half-lives and high volumes of distribution. Based on pharmacokinetic testing and lack of toxicity in vivo, 9a remained the series lead. 9a exerted a lengthy post antibiotic effect and was highly active against nonreplicating M. tuberculosis grown under hypoxia. 9a showed a low potential for cross resistance to current antitubercular agents, and a mechanism of activation distinct from pre-clinical tuberculosis candidates PA-824 and OPC-67683. Together these studies show that 9a is a nanomolar inhibitor of actively growing as well as nonreplicating M. tuberculosis.


Assuntos
Antituberculosos , Compostos Heterocíclicos de 4 ou mais Anéis , Mycobacterium tuberculosis/metabolismo , Nitrofuranos , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacocinética , Antituberculosos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Nitrofuranos/síntese química , Nitrofuranos/química , Nitrofuranos/farmacocinética , Nitrofuranos/farmacologia , Tuberculose/tratamento farmacológico
15.
Chem Biol ; 20(3): 370-8, 2013 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-23521795

RESUMO

Identification of unique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglected diseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data to experimentally validate a virtual screening approach employing Bayesian models built with bioactivity information (single-event model) as well as bioactivity and cytotoxicity information (dual-event model). We virtually screened a commercial library and experimentally confirmed actives with hit rates exceeding typical HTS results by one to two orders of magnitude. This initial dual-event Bayesian model identified compounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a published set of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of a drug lead. These Bayesian models offer significant economies in time and cost to drug discovery.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/toxicidade , Descoberta de Drogas , Animais , Teorema de Bayes , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Feminino , Concentração Inibidora 50 , Macrófagos/efeitos dos fármacos , Camundongos , Mycobacterium tuberculosis/efeitos dos fármacos , Células Vero
16.
Infect Agent Cancer ; 7(1): 14, 2012 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-22709446

RESUMO

BACKGROUND: Compounds that can act as agonists for toll-like receptors (TLRs) may be promising candidates for the development of drugs against infectious diseases and cancer. The present study aimed to characterize the immunomodulatory effects of P-MAPA on TLRs in vitro and in vivo, as well as to investigate its potential as adjuvant therapy in infectious diseases and cancer. METHODS: For these purposes, the activity of P-MAPA on TLRs was assayed in vitro through NF-κB activation in HEK293 cells expressing a given TLR, and using an in vivo animal model for bladder cancer (BC). The antimicrobial activity of P-MAPA was tested against Mycobacterium tuberculosis (TB) in vitro in an MIC assay, and in vivo using an aerosol infection model of murine tuberculosis. Antitumor effects of P-MAPA were tested in an animal model with experimentally induced BC. Moxifloxacin (MXF) and Bacillus Calmette-Guerin (BCG) were used as positive controls in the animal models. RESULTS: The results showed that P-MAPA, administered alone or in combination with MXF, induced significant responses in vivo against TB. In contrast, the compound did not show antimicrobial activity in vitro. P-MAPA showed a significant stimulatory effect on human TLR2 and TLR4 in vitro. In BC, TLR2, TLR4 and p53 protein levels were significantly higher in the P-MAPA group than in the BCG group. The most common histopathological changes in each group were papillary carcinoma in BC group, low-grade intraepithelial neoplasia in BCG group and simple hyperplasia in P-MAPA group. Concerning the toxicological analysis performed during BC treatment, P-MAPA did not show evidence for hepatotoxicity and nephrotoxicity. CONCLUSIONS: In conclusion, P-MAPA acted as TLR ligand in vitro and improved the immunological status in BC, increasing TLR2 and TLR4 protein levels. P-MAPA immunotherapy was more effective in restoring p53 and TLRs reactivities and showed significantly greater antitumor activity than BCG. The activation of TLRs and p53 may provide a hypothetical mechanism for the therapeutic effects in both cancer and infectious diseases. Taken together data obtained will encourage the further investigation of P-MAPA as a potential candidate for the treatment of cancer and infectious diseases.

17.
Antimicrob Agents Chemother ; 52(4): 1513-5, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18268091

RESUMO

A novel subclass of quinolones, 2-pyridones, showed potent activity against Mycobacterium tuberculosis, with KRQ-10018 being an early lead. KRQ-10018 showed better activity in vitro against M. tuberculosis versus moxifloxacin. In vivo efficacy of KRQ-10018 at 300 mg/kg of body weight was similar to that of isoniazid at 25 mg/kg, but showed less activity than moxifloxacin at 300 mg/kg.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Piridonas/farmacologia , Piridonas/uso terapêutico , Tuberculose Pulmonar/tratamento farmacológico , Animais , Antituberculosos/administração & dosagem , Disponibilidade Biológica , Interferon gama/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Testes de Sensibilidade Microbiana , Piridonas/administração & dosagem , Quinolonas/administração & dosagem , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Resultado do Tratamento , Tuberculose Pulmonar/microbiologia
18.
Infect Immun ; 75(5): 2621-5, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17283091

RESUMO

Cultures of Mycobacterium tuberculosis grown under oxygen depletion conditions enter into a state of nonreplicating persistence that may reflect a physiologically latent state. When these cultures were harvested and injected intranasally into mice, no bacteria could be recovered from the lungs for about 3 weeks, but after that evidence of regrowth was observed. Preimmunization of mice with a panel of selected vaccine candidates slowed or prevented this event. This simple model has potential for identifying vaccines targeting latent tuberculosis.


Assuntos
Adaptação Fisiológica , Modelos Animais de Doenças , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Oxigênio/farmacologia , Tuberculose Pulmonar/patologia , Animais , Feminino , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/fisiologia , Organismos Livres de Patógenos Específicos , Tuberculose Pulmonar/microbiologia
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