RESUMO
Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-ß-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Hidantoínas/química , Actinobacteria/efeitos dos fármacos , Oxirredutases do Álcool/metabolismo , Proteínas de Bactérias/metabolismo , Estabilidade de Medicamentos , Inibidores Enzimáticos/química , Células Hep G2 , Ensaios de Triagem em Larga Escala/métodos , Humanos , Macrófagos/microbiologia , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Reprodutibilidade dos Testes , Relação Estrutura-Atividade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologiaRESUMO
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
Assuntos
Antituberculosos/farmacologia , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Animais , Antituberculosos/química , Sítios de Ligação , Domínio Catalítico , Modelos Animais de Doenças , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/genética , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Inibidores Enzimáticos/química , Feminino , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Microssomos , Modelos Moleculares , Mutação , Mycobacterium tuberculosis/genética , Ligação Proteica , Conformação Proteica , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/mortalidade , Tuberculose Resistente a Múltiplos MedicamentosRESUMO
The concept of antimicrobial susceptibility testing is an essential part of clinical microbiology. Antimicrobial testing has played a central role in the identification of new antibiotics and defining their clinical uses. Here we describe different approaches to determine the activity of compounds in medium- or high-throughput format.
