RESUMO
This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).
Assuntos
Antibacterianos/síntese química , Pirrolidinas/síntese química , Tetraciclinas/síntese química , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Ciclofosfamida , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli/tratamento farmacológico , Infecções por Escherichia coli/etiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Masculino , Resistência a Meticilina , Camundongos , Testes de Sensibilidade Microbiana , Neutropenia/induzido quimicamente , Neutropenia/complicações , Pirrolidinas/química , Pirrolidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Sepse/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Resistência a Tetraciclina , Tetraciclinas/química , Tetraciclinas/farmacologiaRESUMO
Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.
Assuntos
Antibacterianos/síntese química , Tetraciclinas/síntese química , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Disponibilidade Biológica , Ciclofosfamida , Farmacorresistência Bacteriana Múltipla , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Ratos , Ratos Sprague-Dawley , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/etiologia , Infecções Respiratórias/microbiologia , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Sepse/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Resistência a Tetraciclina , Tetraciclinas/química , Tetraciclinas/farmacologiaRESUMO
Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Tetraciclinas/síntese química , Tetraciclinas/farmacologia , Animais , Antibacterianos/química , Área Sob a Curva , Macaca fascicularis , Camundongos , Estrutura Molecular , Terapia de Alvo Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetraciclinas/químicaRESUMO
A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.
Assuntos
Antibacterianos/síntese química , Compostos Aza/síntese química , Tetraciclinas/síntese química , Administração Oral , Animais , Antibacterianos/química , Antibacterianos/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Disponibilidade Biológica , Infecções por Escherichia coli/prevenção & controle , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Injeções Intravenosas , Camundongos , Testes de Sensibilidade Microbiana , Ratos , Ratos Sprague-Dawley , Sepse/prevenção & controle , Infecções Estreptocócicas/prevenção & controle , Relação Estrutura-Atividade , Resistência a Tetraciclina/efeitos dos fármacos , Tetraciclinas/química , Tetraciclinas/farmacologiaRESUMO
We found recently that, in yeast cells, the heterologous expression of Bax induces a loss of plating efficiency different from that induced by acute stress because it is associated with the maintenance of plasma membrane integrity (Camougrand, N., Grelaud-Coq, A., Marza, E., Priault, M., Bessoule, J. J., and Manon, S. (2003) Mol. Microbiol. 47, 495-506). Bax effects were neither dependent on the presence of the yeast metacaspase Yca1p and the apoptosis-inducing factor homolog nor associated with the appearance of typical apoptotic markers such as metacaspase activation, annexin V binding, and DNA cleavage. Yeast cells expressing Bax instead displayed autophagic features, including increased accumulation of Atg8p, activation of vacuolar alkaline phosphatase, and the presence of autophagosomes and autophagic bodies. However, the inactivation of autophagy did not prevent and actually slightly accelerated Bax-induced loss of plating efficiency. On the other hand, Bax expression induced a fragmentation of the mitochondrial network, which retained, however, some level of organization in wild-type cells. However, when expressed in cells inactivated for the gene UTH1, previously shown to be involved in mitophagy, Bax induced a complete disorganization of the mitochondrial network. Interestingly, although mitochondrially targeted green fluorescent protein was slowly degraded in the wild-type strain, it remained unaffected in the mutant. Furthermore, the slow loss of plating efficiency in the mutant strain correlated with a loss of plasma membrane integrity. These data suggest that Bax-induced loss of growth capacity is associated with maintenance of plasma membrane integrity dependent on UTH1, suggesting that selective degradation of altered mitochondria is required for a regulated loss of growth capacity.