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1.
Tuberculosis (Edinb) ; 88(5): 420-9, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18479968

RESUMO

A temperature sensitive mutation in the cell division protein FtsZ was used in combination with transcriptional analysis to identify biomarkers for inhibition of septum formation. Crystallography and modeling revealed that the glycine for aspartate substitution at amino acid 210 was located in helix 8 of the protein, adjacent to the T7 synergy loop. To verify the molecular behavior of FtsZ D210G, the in vitro activity and structural stability were evaluated as a function of temperature. These analyses confirmed that the FtsZ D210G mutant had reduced GTPase and polymerization activity compared to wild-type FtsZ, and CD spectroscopy demonstrated that both FtsZ D210G and wild-type FtsZ had similar structure and stability. Significantly, the FtsZ D210G merodiploid strain of M. tuberculosis had compromised growth at 37 degrees C, substantiating the suitability of FtsZ D210G as a molecular tool for global analysis in response to improper FtsZ polymerization and septum inhibition. Advanced model-based bioinformatics and transcriptional mapping were used to identify high-content multiple features that provide biomarkers for the development of a rational drug screening platform for discovering novel chemotherapeutics that target cell division.


Assuntos
Proteínas de Bactérias/biossíntese , Proteínas do Citoesqueleto/biossíntese , GTP Fosfo-Hidrolases/biossíntese , Mycobacterium tuberculosis/genética , Proteínas de Bactérias/química , Ciclo Celular , Divisão Celular , Dicroísmo Circular/métodos , Cristalografia por Raios X/métodos , Proteínas do Citoesqueleto/química , Regulação Bacteriana da Expressão Gênica , Humanos , Mutagênese Sítio-Dirigida , Mycobacterium tuberculosis/fisiologia , Transcrição Gênica
2.
J Med Chem ; 49(2): 463-6, 2006 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-16420032

RESUMO

Screening of 120 taxanes identified a number of compounds that exhibited significant antituberculosis activity. Rational optimization of selected compounds led to the discovery that the C-seco-taxane-multidrug-resistance (MDR) reversal agents (C-seco-TRAs) are noncytotoxic at the upper limit of solubility and detection (>80 microM), while maintaining MIC(99) values of 1.25-2.5 microM against drug-resistant and drug-sensitive strains of Mycobacterium tuberculosis (MTB). Treatment of MTB cells with TRA 3aa and 10a at the MIC caused filamentation and prolongation of the cells, a phenotypic response to FtsZ inactivation.


Assuntos
Antituberculosos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Taxoides/síntese química , Citoesqueleto de Actina/efeitos dos fármacos , Citoesqueleto de Actina/ultraestrutura , Antineoplásicos/farmacologia , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Biopolímeros , Proteínas do Citoesqueleto/química , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/ultraestrutura , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Taxoides/química , Taxoides/farmacologia
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