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1.
Bioorg Med Chem ; 62: 116722, 2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35358864

RESUMO

Early efforts to broaden the spectrum and potency of cyclic boronic acid ß-lactamase inhibitor vaborbactam included a series of 7-membered ring boronates. Exploration of stereoisomers and incorporation of heteroatoms allowed identification of the all-carbon cyclic boronate with substituents trans as the preferred core structure, showing inhibition of Class A and C enzymes. Crystal structures of one analog bound to important ß-lactamase enzymes were obtained. When isolated under acidic conditions, these compounds spontaneously formed a neutral cyclic anhydride (intramolecular prodrug) which was shown to have much-improved oral bioavailability (52-69%) compared to the ring-opened carboxylate salt (9%).


Assuntos
Pró-Fármacos , Inibidores de beta-Lactamases , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Pró-Fármacos/farmacologia , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/metabolismo
2.
J Med Chem ; 64(23): 17523-17529, 2021 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-34817182

RESUMO

In recognition of the need for effective oral therapies to treat Gram-negative bacterial infections, efforts were directed toward identifying an oral prodrug of ß-lactamase inhibitor clinical candidate QPX7728. Seventeen prodrugs were synthesized; key properties investigated were rates of cleavage to the active form in vitro, pharmacokinetics across species, and crystallinity. Compound 5-Na (QPX7831 Sodium) emerged with optimal properties across all key attributes.


Assuntos
Ácidos Borínicos/farmacologia , Ácidos Carboxílicos/farmacologia , Pró-Fármacos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Humanos
3.
Antimicrob Agents Chemother ; 64(11)2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32839224

RESUMO

Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.


Assuntos
Enterobacteriáceas Resistentes a Carbapenêmicos , Klebsiella pneumoniae , Animais , Antibacterianos/farmacologia , Carbapenêmicos/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases/genética , beta-Lactamas
4.
J Med Chem ; 63(14): 7491-7507, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32150407

RESUMO

Despite major advances in the ß-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are the class B (metallo) enzyme NDM-1 of Enterobacteriaceae and the class D (OXA) enzymes of Acinetobacter baumannii. Continuing the boronic acid program that led to vaborbactam, efforts were directed toward expanding the spectrum to allow treatment of a wider range of organisms. Through key structural modifications of a bicyclic lead, stepwise gains in spectrum of inhibition were achieved, ultimately resulting in QPX7728 (35). This compound displays a remarkably broad spectrum of inhibition, including class B and class D enzymes, and is little affected by porin modifications and efflux. Compound 35 is a promising agent for use in combination with a ß-lactam antibiotic for the treatment of a wide range of multidrug resistant Gram-negative bacterial infections, by both intravenous and oral administration.


Assuntos
Ácidos Borínicos/farmacologia , Ácidos Borônicos/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores de beta-Lactamases/farmacologia , Animais , Bactérias/efeitos dos fármacos , Ácidos Borínicos/química , Ácidos Borínicos/farmacocinética , Ácidos Borínicos/uso terapêutico , Ácidos Borônicos/química , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/uso terapêutico , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/uso terapêutico , Descoberta de Drogas , Infecções por Klebsiella/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/química , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/uso terapêutico
5.
Artigo em Inglês | MEDLINE | ID: mdl-31988101

RESUMO

Acinetobacter baumannii infections are difficult to treat and have limited treatment options. Carbapenems, including meropenem, are currently considered the first-line agents for the treatment of infections caused by Acinetobacter spp. The percentage of a 24-hour period that the concentration of free drug in plasma is above the MIC (%24-h fT>MIC) to achieve stasis, 1 log CFU, or 2 log CFU of bacterial killing against A. baumannii has not been studied previously for meropenem. The objective of this study was to determine these parameters for meropenem against A. baumannii in a neutropenic mouse thigh infection model. Six A. baumannii clinical isolates with MICs ranging from 0.25 to 16 mg/liter were tested. Meropenem produced a bacteriostatic effect with a %24-h fT>MIC of 7 to 24% and produced 1 log CFU of bacterial killing with a %24-h fT>MIC of 15 to 37%.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/farmacocinética , Meropeném/farmacocinética , Infecções por Acinetobacter/microbiologia , Animais , Antibacterianos/sangue , Antibacterianos/farmacologia , Carga Bacteriana , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Feminino , Meropeném/sangue , Meropeném/farmacologia , Camundongos , Testes de Sensibilidade Microbiana
6.
Artigo em Inglês | MEDLINE | ID: mdl-30323049

RESUMO

We have evaluated the activity of meropenem-vaborbactam against clinical isolates of Pseudomonas aeruginosaandAcinetobacter baumannii in a neutropenic mouse thigh infection model. Data show that meropenem-vaborbactam regimens equivalent to 3-h infusions every 8 h with 2 g meropenem and 2 g vaborbactam produced bacterial killing against strains with MICs of 2 to 16 mg/liter and suggests that this combination may have utility in the treatment of infections caused by P. aeruginosa and A. baumannii.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Meropeném/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Acinetobacter baumannii/isolamento & purificação , Animais , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/isolamento & purificação
7.
Artigo em Inglês | MEDLINE | ID: mdl-30397059

RESUMO

Minocycline is currently approved in the United States for the treatment of infections caused by susceptible isolates of Acinetobacter spp. The objective of these studies was to determine the minocycline exposures associated with an antibacterial effect against Acinetobacter baumannii in a rat pneumonia model. Rats received minocycline doses as 30-min intravenous infusions. In the rat pneumonia model, six clinical isolates of A. baumannii with MICs ranging from 0.03 to 4 mg/liter were studied. In this model, minocycline produced a bacteriostatic effect with a free 24-h area under the concentration-time curve (AUC)/MIC ratio of 10 to 16 and produced 1 log of bacterial killing with a free 24-h AUC/MIC of 13 to 24. These exposures can be achieved with the current FDA-approved dosage regimens of intravenous minocycline.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Minociclina/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/microbiologia , Animais , Ciclofosfamida/farmacocinética , Ciclofosfamida/uso terapêutico , Masculino , Minociclina/farmacocinética , Ratos , Ratos Sprague-Dawley
8.
Artigo em Inglês | MEDLINE | ID: mdl-30397063

RESUMO

Vaborbactam is a novel beta-lactamase inhibitor with activity against important beta-lactamases, in particular, serine carbapenemases, and is currently approved in combination with meropenem as Vabomere for the treatment of complicated urinary tract infections, including pyelonephritis. This combination is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate vaborbactam pharmacokinetics (PK) and pharmacodynamics (PD) relationships for efficacy in a neutropenic mouse thigh infection model, as well as in an in vitro hollow-fiber infection model, in combination with a fixed exposure of meropenem using KPC-containing strains of Enterobacteriaceae For both models, the meropenem dosage regimen was designed to simulate a 2-g dose administered every eight hours (q8h) by 3-h infusion. Vaborbactam dosage regimens were designed to produce a wide range of 24-h areas under the concentration-time curves (AUCs) in the thigh infection model. However, for the hollow-fiber model, the AUCs were limited to values of 192, 320, or 550 mg · h/liter. In both the animal and in vitro models, the PK-PD parameter that best described the antibacterial activity of vaborbactam, when administered in combination with meropenem at exposures equivalent to 2 g dosed q8h by 3-h infusion in humans, was the 24-h free vaborbactam AUC/meropenem-vaborbactam (with vaborbactam at 8 mg/liter) MIC ratio. The magnitude of this ratio for bacteriostasis was 9 to 12 and the magnitude to observe a 1-log kill was 18 to 38. In addition, a magnitude greater than 24 suppressed the development of resistance in the in vitro hollow-fiber model.


Assuntos
Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Ácidos Borônicos/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacologia , Compostos Heterocíclicos com 1 Anel/farmacocinética , Meropeném/farmacologia , Meropeném/farmacocinética , Infecções Urinárias/tratamento farmacológico , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/farmacocinética , Animais , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Modelos Animais de Doenças , Combinação de Medicamentos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Feminino , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Neutropenia/microbiologia , Pielonefrite/tratamento farmacológico , Pielonefrite/microbiologia , Infecções Urinárias/microbiologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-29109160

RESUMO

Meropenem-vaborbactam (Vabomere) is highly active against Gram-negative pathogens, especially Klebsiella pneumoniae carbapenemase (KPC)-producing, carbapenem-resistant Enterobacteriaceae The objective of these studies was to evaluate the efficacy of meropenem alone and in combination with vaborbactam in mouse thigh and lung infection models. Thighs or lungs of neutropenic mice were infected with KPC-producing carbapenem-resistant Enterobacteriaceae, with meropenem MICs ranging from ≤0.06 to 8 mg/liter in the presence of 8 mg/liter vaborbactam. Mice were treated with meropenem alone or meropenem in combination with vaborbactam every 2 h for 24 h to provide exposures comparable to 2-g doses of each component in humans. Meropenem administered in combination with vaborbactam produced bacterial killing in all strains tested, while treatment with meropenem alone either produced less than 0.5 log CFU/tissue of bacterial killing or none at all. In the thigh model, 11 strains were treated with the combination of meropenem plus vaborbactam (300 plus 50 mg/kg of body weight). This combination produced from 0.8 to 2.89 logs of bacterial killing compared to untreated controls at the start of treatment. In the lung infection model, two strains were treated with the same dosage regimen of meropenem and vaborbactam. The combination produced more than 1.83 logs of bacterial killing against both strains tested compared to untreated controls at the start of treatment. Overall, these data suggest that meropenem-vaborbactam may have utility in the treatment of infections due to KPC-producing carbapenem-resistant Enterobacteriaceae.


Assuntos
Antibacterianos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Enterobacter cloacae/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Klebsiella pneumoniae/efeitos dos fármacos , Meropeném/uso terapêutico , Infecções Respiratórias/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Inibidores de beta-Lactamases/uso terapêutico , Animais , Antibacterianos/farmacocinética , Proteínas de Bactérias/metabolismo , Ácidos Borônicos/farmacocinética , Enterobacteriáceas Resistentes a Carbapenêmicos/isolamento & purificação , Modelos Animais de Doenças , Combinação de Medicamentos , Feminino , Humanos , Meropeném/farmacocinética , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Infecções Respiratórias/microbiologia , Infecções Respiratórias/patologia , Infecções dos Tecidos Moles/microbiologia , Coxa da Perna/microbiologia , Coxa da Perna/patologia , Inibidores de beta-Lactamases/farmacocinética , beta-Lactamases/metabolismo
10.
Artigo em Inglês | MEDLINE | ID: mdl-29133570

RESUMO

The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.


Assuntos
Antibacterianos/farmacologia , Ácidos Borônicos/farmacologia , Enterobacteriáceas Resistentes a Carbapenêmicos/efeitos dos fármacos , Infecções por Enterobacteriaceae/tratamento farmacológico , Meropeném/farmacologia , Proteínas de Bactérias/metabolismo , Infecções por Enterobacteriaceae/metabolismo , Humanos , Testes de Sensibilidade Microbiana/métodos
11.
J Med Chem ; 58(9): 3682-92, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25782055

RESUMO

The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness of the ß-lactam class of antimicrobials. A program was initiated to discover a new series of serine ß-lactamase inhibitors containing a boronic acid pharmacophore, with the goal of finding a potent inhibitor of serine carbapenemase enzymes that are currently compromising the utility of the carbapenem class of antibacterials. Potential lead structures were screened in silico by modeling into the active sites of key serine ß-lactamases. Promising candidate molecules were synthesized and evaluated in biochemical and whole-cell assays. Inhibitors were identified with potent inhibition of serine carbapenemases, particularly the Klebsiella pneumoniae carbapenemase (KPC), with no inhibition of mammalian serine proteases. Studies in vitro and in vivo show that RPX7009 (9f) is a broad-spectrum inhibitor, notably restoring the activity of carbapenems against KPC-producing strains. Combined with a carbapenem, 9f is a promising product for the treatment of multidrug resistant Gram-negative bacteria.


Assuntos
Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Ácidos Borônicos/química , Compostos Heterocíclicos com 1 Anel/química , Inibidores de beta-Lactamases/química , Animais , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ácidos Borônicos/farmacocinética , Ácidos Borônicos/farmacologia , Carbapenêmicos/farmacologia , Cristalografia por Raios X , Farmacorresistência Bacteriana , Sinergismo Farmacológico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/isolamento & purificação , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 1 Anel/farmacologia , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Inibidores de beta-Lactamases/farmacocinética , Inibidores de beta-Lactamases/farmacologia , beta-Lactamases
12.
FEMS Immunol Med Microbiol ; 61(2): 141-6, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21073547

RESUMO

Inflammation resulting from chronic bacterial infection in the lung contributes to long-term pulmonary complications in chronic pulmonary infections such as cystic fibrosis. Aerosol administration of levofloxacin as in the form of the investigational formulation MP-376 results in higher concentrations in lung tissues that are higher than those that can be attained with oral or intravenous dosing of levofloxacin. The objective of this study was to evaluate the effect of high concentrations of levofloxacin achieved with aerosol administration of MP-376 on proinflammatory cytokine secretion by immortalized human bronchial epithelia cells in vitro. Additionally, we investigated the potential mechanisms of the immunomodulatory effect of levofloxacin. In vitro studies in human lung epithelial cell lines showed that levofloxacin led to a dose-related reduction in IL-6 and IL-8 concentrations, with 300 µg mL(-1) resulting in the reduction of levels of IL-6 by fourfold and IL-8 by twofold (P<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. Levofloxacin treatment did not affect the cytokine mRNA level and nuclear factor-κB-dependent promoter activity. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following the administration of aerosol MP-376 may provide additional benefits in patients with chronic pulmonary infections that are independent of its antibacterial properties.


Assuntos
Anti-Inflamatórios/farmacologia , Células Epiteliais/efeitos dos fármacos , Interleucina-6/antagonistas & inibidores , Interleucina-8/antagonistas & inibidores , Levofloxacino , Ofloxacino/farmacologia , Administração por Inalação , Aerossóis/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Linhagem Celular , Doença Crônica , Perfilação da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Ofloxacino/administração & dosagem , Pneumonia/tratamento farmacológico , Tobramicina/farmacologia
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