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1.
Clin Pharmacol Ther ; 109(4): 1000-1020, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33576025

RESUMO

Multidrug-resistant bacteria are causing a serious global health crisis. A dramatic decline in antibiotic discovery and development investment by pharmaceutical industry over the last decades has slowed the adoption of new technologies. It is imperative that we create new mechanistic insights based on latest technologies, and use translational strategies to optimize patient therapy. Although drug development has relied on minimal inhibitory concentration testing and established in vitro and mouse infection models, the limited understanding of outer membrane permeability in Gram-negative bacteria presents major challenges. Our team has developed a platform using the latest technologies to characterize target site penetration and receptor binding in intact bacteria that inform translational modeling and guide new discovery. Enhanced assays can quantify the outer membrane permeability of ß-lactam antibiotics and ß-lactamase inhibitors using multiplex liquid chromatography tandem mass spectrometry. While ß-lactam antibiotics are known to bind to multiple different penicillin-binding proteins (PBPs), their binding profiles are almost always studied in lysed bacteria. Novel assays for PBP binding in the periplasm of intact bacteria were developed and proteins identified via proteomics. To characterize bacterial morphology changes in response to PBP binding, high-throughput flow cytometry and time-lapse confocal microscopy with fluorescent probes provide unprecedented mechanistic insights. Moreover, novel assays to quantify cytosolic receptor binding and intracellular drug concentrations inform target site occupancy. These mechanistic data are integrated by quantitative and systems pharmacology modeling to maximize bacterial killing and minimize resistance in in vitro and mouse infection models. This translational approach holds promise to identify antibiotic combination dosing strategies for patients with serious infections.


Assuntos
Técnicas Bacteriológicas/métodos , Descoberta de Drogas/métodos , Farmacorresistência Bacteriana Múltipla/fisiologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/fisiologia , Animais , Membrana Celular/fisiologia , Modelos Animais de Doenças , Humanos , Modelos Teóricos , Proteínas de Ligação às Penicilinas/fisiologia , beta-Lactamas/farmacologia
2.
Science ; 324(5928): 801-4, 2009 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-19299584

RESUMO

New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.


Assuntos
Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Polissacarídeos/biossíntese , Racemases e Epimerases/antagonistas & inibidores , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Tiazinas/farmacologia , Tiazinas/uso terapêutico , Tuberculose/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Arabinose/metabolismo , Parede Celular/metabolismo , Farmacorresistência Bacteriana , Inibidores Enzimáticos/líquido cefalorraquidiano , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Etambutol/farmacologia , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes Bacterianos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Estrutura Molecular , Mycobacterium/efeitos dos fármacos , Mycobacterium/genética , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Racemases e Epimerases/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Tiazinas/síntese química , Tiazinas/química , Tuberculose/microbiologia
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