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1.
Nature ; 593(7859): 424-428, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33767445

RESUMO

Neutralizing antibodies that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein are among the most promising approaches against COVID-191,2. A bispecific IgG1-like molecule (CoV-X2) has been developed on the basis of C121 and C135, two antibodies derived from donors who had recovered from COVID-193. Here we show that CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable spike binding to the cellular receptor of the virus, angiotensin-converting enzyme 2 (ACE2). Furthermore, CoV-X2 neutralizes wild-type SARS-CoV-2 and its variants of concern, as well as escape mutants generated by the parental monoclonal antibodies. We also found that in a mouse model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, the simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, and combines the advantages of antibody cocktails with those of single-molecule approaches.


Assuntos
Anticorpos Biespecíficos/imunologia , Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , COVID-19/virologia , Imunoglobulina G/imunologia , SARS-CoV-2/imunologia , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/uso terapêutico , Peso Corporal , COVID-19/prevenção & controle , Dependovirus/genética , Modelos Animais de Doenças , Epitopos de Linfócito B/química , Epitopos de Linfócito B/imunologia , Feminino , Humanos , Evasão da Resposta Imune/genética , Camundongos , Camundongos Endogâmicos C57BL , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Tratamento Farmacológico da COVID-19
2.
Small ; 18(28): e2201853, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35691939

RESUMO

In this work, levofloxacin (LVX), a third-generation fluoroquinolone antibiotic, is encapsulated within amphiphilic polymeric nanoparticles of a chitosan-g-poly(methyl methacrylate) produced by self-assembly and physically stabilized by ionotropic crosslinking with sodium tripolyphosphate. Non-crosslinked nanoparticles display a size of 29 nm and a zeta-potential of +36 mV, while the crosslinked counterparts display 45 nm and +24 mV, respectively. The cell compatibility, uptake, and intracellular trafficking are characterized in the murine alveolar macrophage cell line MH-S and the human bronchial epithelial cell line BEAS-2B in vitro. Internalization events are detected after 10 min and the uptake is inhibited by several endocytosis inhibitors, indicating the involvement of complex endocytic pathways. In addition, the nanoparticles are detected in the lysosomal compartment. Then, the antibacterial efficacy of LVX-loaded nanoformulations (50% w/w drug content) is assessed in MH-S and BEAS-2B cells infected with Staphylococcus aureus and the bacterial burden is decreased by 49% and 46%, respectively. In contrast, free LVX leads to a decrease of 8% and 5%, respectively, in the same infected cell lines. Finally, intravenous injection to a zebrafish larval model shows that the nanoparticles accumulate in macrophages and endothelium and demonstrate the promise of these amphiphilic nanoparticles to target intracellular infections.


Assuntos
Quitosana , Nanopartículas , Animais , Antibacterianos/farmacologia , Humanos , Macrófagos/metabolismo , Camundongos , Peixe-Zebra
4.
Biomacromolecules ; 20(4): 1798-1815, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30785284

RESUMO

Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of alveolar macrophages. These cells avidly take up nanoparticles, even without the use of specific targeting ligands, making the use of nanotherapeutics ideal for the treatment of such infections. Methoxy poly(ethylene oxide)- block-poly(ε-caprolactone) nanoparticles of several different polymer blocks' molecular weights and sizes (20-110 nm) were developed and critically compared as carriers for rifampicin, a cornerstone in tuberculosis therapy. The polymeric nanoparticles' uptake, consequent organelle targeting and intracellular degradation were shown to be highly dependent on the nanoparticles' physicochemical properties (the cell uptake half-lives 2.4-21 min, the degradation half-lives 51.6 min-ca. 20 h after the internalization). We show that the nanoparticles are efficiently taken up by macrophages and are able to effectively neutralize the persisting bacilli. Finally, we demonstrate, using a zebrafish model of tuberculosis, that the nanoparticles are well tolerated, have a curative effect, and are significantly more efficient compared to a free form of rifampicin. Hence, these findings demonstrate that this system shows great promise, both in vitro and in vivo, for the treatment of tuberculosis.


Assuntos
Portadores de Fármacos , Macrófagos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Nanopartículas , Rifampina , Tuberculose/tratamento farmacológico , Animais , Modelos Animais de Doenças , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Humanos , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Nanopartículas/química , Nanopartículas/uso terapêutico , Células RAW 264.7 , Rifampina/química , Rifampina/farmacocinética , Rifampina/farmacologia , Tuberculose/metabolismo , Tuberculose/patologia , Peixe-Zebra
5.
Bioorg Med Chem ; 25(20): 5468-5476, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28835350

RESUMO

In this work, four series of tertiary amine-containing derivatives of 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents were prepared, and their in vitro antimycobacterial effects were evaluated. We found that the studied compounds showed lipophilicity-dependent antimycobacterial activity. The N-benzylpiperazine derivatives, which had the highest lipophilicity among all of the series, showed the highest in vitro antimycobacterial activities against Mycobacterium tuberculosis CNCTC My 331/88 (H37Rv), comparable to those of the first-line drugs isoniazid and rifampicin. The presence of two tertiary amines in these N-benzylpiperazine derivatives enabled us to prepare water-soluble dihydrochloride salts, overcoming the serious drawback of previously described 3,5-dinitrophenyl tetrazole and oxadiazole lead compounds. The water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents described in this work are good candidates for further in vitro and in vivo pharmacokinetic and pharmacodynamic studies.


Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Oxidiazóis/farmacologia , Tetrazóis/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Células CACO-2 , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Relação Dose-Resposta a Droga , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Solubilidade , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/química , Água/química
6.
Neuro Endocrinol Lett ; 34 Suppl 2: 134-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24362106

RESUMO

OBJECTIVES: Tacrine is an inhibitor of acetylcholinestrase (AChE) formerly used to treat cognitive impairment of Alzheimer disease. In previous works, we have shown that inhibitors of AChE can modulate innate immunity responses. In the present study we focused on modulation of adaptive immunity represented by production of antibodies. It is hypothesized that the cholinergic anti-inflammatory pathway is a common mechanism how inhibitors of AChE can influence immunity. Here, tularemia is used as a model disease for experimental purposes. DESIGN: A total of 64 BALB/c mice were divided into eight groups. The animals received a dose of tacrine 0.1-0.5 mg/kg with combination of saline or inoculum of Francisella tularensis. The doses of tacrine were derived from clinical trials. The animals were sacrificed after three days and total antibodies in plasma and bacterial burden in the liver were measured. RESULTS: Tacrine did not alter the antibodies level in non-infected animals. Antibodies levels of infected animals administered tacrine were reduced in a dose response manner. Tacrine also caused an increase in total bacteria numbers in the liver. CONCLUSIONS: Tacrine significantly suppressed adaptive immunity represented by the ability of the organism to produce antibodies. We infer that tacrine can modulate the cholinergic anti-inflammatory pathway by a mechanism based on inhibition of blood AChE followed by higher availability of acetylcholine. The anti-inflammatory pathway is then stimulated and the body is not able to simply resolve antigen. Application of an AChE inhibitor during infectious diseases can have detrimental consequences for the immune system.


Assuntos
Anticorpos Antibacterianos/sangue , Formação de Anticorpos/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Francisella tularensis/imunologia , Tacrina/farmacologia , Tularemia/imunologia , Animais , Relação Dose-Resposta a Droga , Feminino , Francisella tularensis/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Tularemia/metabolismo
7.
Eur J Med Chem ; 258: 115617, 2023 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-37423128

RESUMO

Tuberculosis is the number one killer of infectious diseases caused by a single microbe, namely Mycobacterium tuberculosis (Mtb). The success rate of curing this infection is decreasing due to emerging antimicrobial resistance. Therefore, novel treatments are urgently needed. As an attempt to develop new antituberculars effective against both drugs-sensitive and drug-resistant Mtb, we report the synthesis of a novel series inspired by combining fragments from the first-line agents isoniazid and pyrazinamide (series I) and isoniazid with the second-line agent 4-aminosalicylic acid (series II). We identified compound 10c from series II with selective, potent in vitro antimycobacterial activity against both drug-sensitive and drug-resistant Mtb H37Rv strains with no in vitro or in vivo cytotoxicity. In the murine model of tuberculosis, compound 10c caused a statistically significant decrease in colony-forming units (CFU) in spleen. Despite having a 4-aminosalicylic acid fragment in its structure, biochemical studies showed that compound 10c does not directly affect the folate pathway but rather methionine metabolism. In silico simulations indicated the possibility of binding to mycobacterial methionine-tRNA synthetase. Metabolic study in human liver microsomes revealed that compound 10c does not have any known toxic metabolites and has a half-life of 630 min, overcoming the main drawbacks of isoniazid (toxic metabolites) and 4-aminosalicylic acid (short half-life).


Assuntos
Ácido Aminossalicílico , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Isoniazida/farmacologia , Ácido Aminossalicílico/farmacologia , Antituberculosos/química , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Metionina , Testes de Sensibilidade Microbiana
8.
ACS Infect Dis ; 9(1): 79-96, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36577009

RESUMO

Apart from the SARS-CoV-2 virus, tuberculosis remains the leading cause of death from a single infectious agent according to the World Health Organization. As part of our long-term research, we prepared a series of hybrid compounds combining pyrazinamide, a first-line antitubercular agent, and 4-aminosalicylic acid (PAS), a second-line agent. Compound 11 was found to be the most potent, with a broad spectrum of antimycobacterial activity and selectivity toward mycobacterial strains over other pathogens. It also retained its in vitro activity against multiple-drug-resistant mycobacterial strains. Several structural modifications were attempted to improve the in vitro antimycobacterial activity. The δ-lactone form of compound 11 (11') had more potent in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Compound 11 was advanced for in vivo studies, where it was proved to be nontoxic in Galleria mellonella and zebrafish models, and it reduced the number of colony-forming units in spleens in the murine model of tuberculosis. Biochemical studies showed that compound 11 targets mycobacterial dihydrofolate reductases (DHFR). An in silico docking study combined with molecular dynamics identified a viable binding mode of compound 11 in mycobacterial DHFR. The lactone 11' opens in human plasma to its parent compound 11 (t1/2 = 21.4 min). Compound 11 was metabolized by human liver fraction by slow hydrolysis of the amidic bond (t1/2 = 187 min) to yield PAS and its starting 6-chloropyrazinoic acid. The long t1/2 of compound 11 overcomes the main drawback of PAS (short t1/2 necessitating frequent administration of high doses of PAS).


Assuntos
Ácido Aminossalicílico , COVID-19 , Mycobacterium tuberculosis , Tuberculose , Humanos , Animais , Camundongos , Pirazinamida/farmacologia , Ácido Aminossalicílico/farmacologia , Peixe-Zebra , SARS-CoV-2 , Antituberculosos/química , Tuberculose/tratamento farmacológico , Lactonas
9.
Microorganisms ; 10(1)2022 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-35056629

RESUMO

Legionnaires' disease is a severe form of lung infection caused by bacteria belonging to the genus Legionella. The disease severity depends on both host immunity and L. pneumophila virulence. The objective of this study was to describe the pathological spectrum of acute pneumonia caused by a virulent clinical isolate of L. pneumophila serogroup 1, sequence type 62. In A/JOlaHsd mice, we compared two infectious doses, namely, 104 and 106 CFU, and their impact on the mouse status, bacterial clearance, lung pathology, and blood count parameters was studied. Acute pneumonia resembling Legionnaires' disease has been described in detail.

10.
Klin Mikrobiol Infekc Lek ; 17(5): 164-7, 2011 Oct.
Artigo em Tcheco | MEDLINE | ID: mdl-22161752

RESUMO

Francisella tularensis belongs to the most important biological agents potentially applicable in biological warfare and bioterrorism. High virulence, easy and rapid spread among individual vectors, stability of the cells in aerosol and good penetration into the lungs make F. tularensis one of the most important biological warfare agents in both human and veterinary medicine. The text provides comprehensive data about tularaemia and outlines the fate of the pathogen in the host. Special attention is paid to immunological aspects of the disease, therapy, and diagnostic methods.


Assuntos
Tularemia/diagnóstico , Guerra Biológica , Francisella tularensis/fisiologia , Humanos , Tularemia/tratamento farmacológico , Tularemia/imunologia , Tularemia/microbiologia
11.
Klin Mikrobiol Infekc Lek ; 17(5): 173-8, 2011 Oct.
Artigo em Tcheco | MEDLINE | ID: mdl-22161754

RESUMO

BACKGROUND: The aim of this study was to evaluate diagnostic sensitivity and specificity of the SERION ELISA classic IgM and SERION ELISA classic IgG kits and to confirm the results by the microagglutination test (MAT). MATERIAL AND METHODS: A total of 45 blood serum samples from 45 patients, 30 from males and 15 from females (mean age 44.24 ± 15.56 range 19-82 year), were included in our study. Blood serum samples were examined using the ELISA and MAT methods and diagnostic sensitivity and specificity of both methods were calculated. RESULTS: The MAT was shown to have 100 % diagnostic sensitivity and specificity. The ELISA kits for detecting IgM and IgG antibodies against pathogenic leptospires had diagnostic sensitivity of 100 % and diagnostic specificity of 88.6 % and 54.3 %, respectively. CONCLUSION: The above results suggest that the MAT with diagnostic sensitivity and specificity of 100 % remains the gold standard for detection of specific antibodies against pathogenic leptospires. The diagnostic sensitivity of both ELISA kits is high but due to their low diagnostic specificity, especially in the case of IgG antibodies, the kits are inappropriate for use in routine clinical practice.


Assuntos
Testes de Aglutinação , Ensaio de Imunoadsorção Enzimática , Leptospirose/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Adulto Jovem
12.
Klin Mikrobiol Infekc Lek ; 17(5): 168-72, 2011 Oct.
Artigo em Tcheco | MEDLINE | ID: mdl-22161753

RESUMO

BACKGROUND: The aim of this study was to evaluate the incidence of leptospirosis in Pardubice and Hradec Králové regions and a part of Vysocina region in 2002-2009. A group of patients was statistically analyzed and the incidence rates of leptospirosis in individual months and years were calculated. MATERIAL AND METHODS: A group of 4,813 patients with suspected leptospirosis from Pardubice and Hradec Králové regions and a part of Vysocina region were examinated in our centre in 2002-2009. A total of 5,366 biological samples were studied. From 4,625 blood samples, 3,958 were examinated with the serological microagglutination-lysis method and the remaining 667 with the PCR method. RESULTS: From 4,813 patients suspected to have leptospirosis, 89 were found to be leptospirosis-positive. Leptospirosis was diagnosed in 63 males (70.7 %) a 26 females (29.3 %); the mean age were 39.52 ± 17.67 years in males and 46.85 ± 18.34 years in females; the mean age men + women was 41.66 ± 18.13 years (range 3-78 years). Most positive male patients (n = 28) were in 26-45 age group; the findings were similar in females (n = 10). The highest number of leptospirosis cases was noted in 2005. Most frequently, infection caused by pathogenic leptospires was diagnosed in November. CONCLUSION: The incidence rates of leptospirosis in Pardubice and Hradec Králové regions and a part of Vysocina region in 2002-2009 (with the exception of 2008) exceeded the overall reported levels 0.4/100,000 population.


Assuntos
Leptospirose/epidemiologia , Adolescente , Adulto , Idoso , Testes de Aglutinação , Criança , Pré-Escolar , República Tcheca/epidemiologia , Feminino , Humanos , Incidência , Leptospirose/diagnóstico , Leptospirose/microbiologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto Jovem
13.
bioRxiv ; 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33501434

RESUMO

Neutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19) 1,2 . We developed a bispecific, IgG1-like molecule (CoV-X2) based on two antibodies derived from COVID-19 convalescent donors, C121 and C135 3 . CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, prevents detectable S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 neutralizes SARS-CoV-2 and its variants of concern, as well as the escape mutants generated by the parental monoclonals. In a novel animal model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

14.
Microorganisms ; 9(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374468

RESUMO

Early detection of biohazardous bacteria that can be misused as biological weapons is one of the most important measures to prevent the spread and outbreak of biological warfare. For this reason, many instrument platforms need to be introduced into operation in the field of biological warfare detection. Therefore the purpose of this study is to establish a new detection panel for biothreat bacteria (Bacillus anthracis, Yersinia pestis, Francisella tularensis, and Brucella spp.) and confirm it by collaborative validation by using a multiplex oligonucleotide ligation followed by polymerase chain reaction and hybridization to microspheres by MagPix detection platform (MOL-PCR). Appropriate specific sequences in bacterial DNA were selected and tested to assemble the detection panel, and MOLigo probes (short specific oligonucleotides) were designed to show no cross-reactivity when tested between bacteria and to decrease the background signal measurement on the MagPix platform. During testing, sensitivity was assessed for all target bacteria using serially diluted DNA and was determined to be at least 0.5 ng/µL. For use as a diagnostic kit and easier handling, the storage stability of ligation premixes (MOLigo probe mixes) was tested. This highly multiplex method can be used for rapid screening to prevent outbreaks arising from the use of bacterial strains for bioterrorism, because time of analysis take under 4 h.

15.
J Control Release ; 321: 312-323, 2020 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-32067995

RESUMO

Tuberculosis represents a major global health problem for which improved approaches are needed to shorten the course of treatment and to combat the emergence of resistant strains. The development of effective and safe nanobead-based interventions can be particularly relevant for increasing the concentrations of antitubercular agents within the infected site and reducing the concentrations in the general circulation, thereby avoiding off-target toxic effects. In this work, rifampicin, a first-line antitubercular agent, was encapsulated into biocompatible and biodegradable polyester-based nanoparticles. In a well-established BALB/c mouse model of pulmonary tuberculosis, the nanoparticles provided improved pharmacokinetics and pharmacodynamics. The nanoparticles were well tolerated and much more efficient than an equivalent amount of free rifampicin.


Assuntos
Antibióticos Antituberculose , Mycobacterium tuberculosis , Rifampina , Tuberculose , Animais , Antibióticos Antituberculose/farmacocinética , Antituberculosos , Portadores de Fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas , Rifampina/farmacocinética , Tuberculose/tratamento farmacológico
16.
Neuro Endocrinol Lett ; 30 Suppl 1: 186-91, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20027169

RESUMO

OBJECTIVES: Bacterium Francisella tularensis is the causative agent of tularemia disease. It is a zoonosis accompanied with high mortality when untreated. Small rodents and hares, in particular, are natural reservoirs of tularemia. Despite physiological similarity of common hosts, tularemia exerts different mortality rates. The pathogenesis of tularemia is still not fully understood. The main pathway is associated with proliferation in macrophages after activation by reactive oxygen species in phagosomes. DESIGN: A fully virulent strain of F. tularensis subsb. holarctica was used for infection of laboratory BALB/c mice (Mus musculus) and common voles (Microtus arvalis) representing murine and microtine species. The total level of low-molecular- weight antioxidants (LMWA) in plasma was assayed by cyclic voltammetry. RESULTS: It was found that common voles are more resistant to tularemia progression when compared to mice. When LMWA assayed, surprising changes in LMWA levels were found. Both mice and common voles were infected with high dose resulting in overall mortality. While there was a quick depletion of LMWA in plasma in mice, common voles were even able to increase LMWA. CONCLUSION: It seems that LMWA play an important role in the organism s protection during tularemia. The ability to compensate the LMWA losses and increase levels of antioxidants in common voles is probably responsible for its lower susceptibility to tularemia.


Assuntos
Antioxidantes/metabolismo , Tularemia/metabolismo , Animais , Arvicolinae , Suscetibilidade a Doenças , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular
17.
J Med Chem ; 62(17): 8115-8139, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31393122

RESUMO

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 µM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-ß-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Desenvolvimento de Medicamentos , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases do Álcool/metabolismo , Antituberculosos/síntese química , Antituberculosos/química , Proteínas de Bactérias/metabolismo , Dinitrobenzenos/síntese química , Dinitrobenzenos/química , Dinitrobenzenos/farmacologia , Relação Dose-Resposta a Droga , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrocarbonetos Fluorados/farmacologia , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/química , Triazóis/farmacologia
19.
Eur J Med Chem ; 126: 369-383, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27907875

RESUMO

Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0.03 µM. Furthermore, these compounds had a highly selective antimycobacterial effect because they were completely inactive against 4 gram positive and 4 gram negative bacteria and eight fungal strains and had low in vitro toxicity for four mammalian cell lines, including hepatic cell lines HepG2 and HuH7. Although the structure-activity relationship study showed that the presence of two nitro groups is highly beneficial for antimycobacterial activity, the analogues with a trifluoromethyl group instead of one of the nitro groups maintained a high antimycobacterial activity, which indicates the possibility for further structural optimization of this class of antitubercular agents.


Assuntos
Desenho de Fármacos , Oxidiazóis/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Tetrazóis/química , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antifúngicos/toxicidade , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Antituberculosos/toxicidade , Resistência a Medicamentos/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/toxicidade
20.
Artigo em Inglês | MEDLINE | ID: mdl-23549511

RESUMO

BACKGROUND: Francisella tularensis is a biological agent exploitable for bioterrorism and biological warfare purposes due to serious pathogenic progression and easy dissemination. Despite intensive research in the past, some adverse consequences remain unclear. One consequence of this pathogen is oxidative stress. AIMS: The aim of this study was to undertake ex vivo assays for monitoring the disease in mice and increase our knowledge of the oxidative stress induced by tularemia. METHODS: The mouse BALB/c model was chosen and the animals were infected by a dose 10(4) CFU of F. tularensis. After five days, the animals were euthanized. Blood immediately processed in plasma, spleen and liver were sampled from the cadavers. Oxidative stress markers, cytokines and histopathological were undertaken. RESULTS: There was a significant link between oxidative stress and tularemia. Particularly elevated levels of malondialdehyde and decreased levels of low molecular weight antioxidants were found in the liver and spleen of tularemia-infected animals. The histopathological findings correlated well with the oxidative stress markers. The liver and spleen were proven to be significantly at risk from the disease and an association between stress and neutrophils in the affected organs was found. The histopathology excluded risk to other organs such as the kidney and or heart. CONCLUSIONS: Oxidative stress plays a significant role in tularemia infection in mice and this was confirmed by the histology.


Assuntos
Fígado/metabolismo , Estresse Oxidativo/fisiologia , Baço/metabolismo , Tularemia/fisiopatologia , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Francisella tularensis , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/patologia , Tularemia/metabolismo , Tularemia/patologia
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