RESUMO
The F1FO-ATP synthase engine is essential for viability and growth of nontuberculous mycobacteria (NTM) by providing the biological energy ATP and keeping ATP homeostasis under hypoxic stress conditions. Here, we report the discovery of the diarylquinoline TBAJ-5307 as a broad spectrum anti-NTM inhibitor, targeting the FO domain of the engine and preventing rotation and proton translocation. TBAJ-5307 is active at low nanomolar concentrations against fast- and slow-growing NTM as well as clinical isolates by depleting intrabacterial ATP. As demonstrated for the fast grower Mycobacterium abscessus, the compound is potent in vitro and in vivo, without inducing toxicity. Combining TBAJ-5307 with anti-NTM antibiotics or the oral tebipenem-avibactam pair showed attractive potentiation. Furthermore, the TBAJ-5307-tebipenem-avibactam cocktail kills the pathogen, suggesting a novel oral combination for the treatment of NTM lung infections.
Assuntos
Antibacterianos , Diarilquinolinas , Inibidores Enzimáticos , Infecções por Mycobacterium não Tuberculosas , Micobactérias não Tuberculosas , Humanos , Trifosfato de Adenosina , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Compostos Azabicíclicos , Carbapenêmicos , Inibidores Enzimáticos/farmacologia , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Diarilquinolinas/farmacologiaRESUMO
The structure of preisomide has been confirmed by total synthesis involving chemoselective oxazine formation and vinyl iodide carbonylation in six steps (longest linear sequence) and 23% overall yield.
RESUMO
The total synthesis of raistrickindole A has been achieved, thereby confirming the proposed structure as an N-hydroxylated DKP. In the first but less selective approach, the DKP was built up by cyclization of a diastereoisomerically mixed N-hydroxylated dipeptide. In the second approach, the same DKP was constructed stereoselectively by the intramolecular Mitsunobu reaction of a hydroxamic acid. The synthesis was completed by a stereoselective oxidative cyclization.
Assuntos
Dipeptídeos , Estrutura Molecular , Ciclização , Oxirredução , EstereoisomerismoRESUMO
The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , ATPases Bacterianas Próton-Translocadoras/antagonistas & inibidores , Diarilquinolinas/farmacologia , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Benzamidas/química , Benzamidas/farmacologia , Benzamidas/toxicidade , Sinergismo Farmacológico , Células-Tronco Embrionárias/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Relação Estrutura-AtividadeRESUMO
The ß-amino acid antibiotic (+)-negamycin has been synthesised in ten steps from epichlorohydrin via Sakurai allylation of an isoxazolidine intermediate. The key allylation reaction proceeded with complete trans-selectivity, which is attributed to electrostatic attraction between the chlorine atom and the iminium ion in the Sakurai intermediate.