RESUMO
Phosphoramidates are becoming increasingly recognized as molecular targets for therapeutic development. Their biological functions are significantly influenced by their inherent properties such as reactivity, as well as the P-N backbone which allows for structural diversity. In this study we report the synthesis of novel carbohydrate-based phosphoramidate derivatives via the Staudinger-phosphite reaction; along with an evaluation of their adjuvant activity in combination with popular antibiotics. Our targets involved variation in both the sugar residue as well as the identity of the phosphoramidate. Moderate to excellent yields of these derivatives were obtained. Notable adjuvant activity was observed with the halogenated phosphoramidates. For the fluorinated glucose derivative in particular, a remarkable 32-fold decrease in the MIC of Ampicillin was obtained against Methicillin-resistant S. aureus.
Assuntos
Amidas/farmacologia , Antibacterianos/farmacologia , Carboidratos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Ácidos Fosfóricos/farmacologia , Amidas/síntese química , Amidas/química , Antibacterianos/síntese química , Antibacterianos/química , Configuração de Carboidratos , Carboidratos/química , Testes de Sensibilidade Microbiana , Ácidos Fosfóricos/síntese química , Ácidos Fosfóricos/químicaRESUMO
In this study, we report the first isolation of three antibiotic indole alkaloid compounds from a Pseudomonad bacterium, Pseudomonas aeruginosa UWI-1. The bacterium was batch fermented in a modified Luria Broth medium and compounds were solvent extracted and isolated by bioassay-guided fractionation. The three compounds were identified as (1) tris(1H-indol-3-yl) methylium, (2) bis(indol-3-yl) phenylmethane, and (3) indolo (2, 1b) quinazoline-6, 12 dione. A combination of 1D and 2D NMR, high-resolution mass spectrometry data and comparison from related data from the literature was used to determine the chemical structures of the compounds. Compounds 1-3 were evaluated in vitro for their antimicrobial activities against a wide range of microorganisms using the broth microdilution technique. Compounds 1 and 2 displayed antibacterial activity against only Gram-positive pathogens, although 1 had significantly lower minimum inhibitory concentration (MIC) values than 2. Compound 3 displayed potent broad-spectrum antimicrobial activity against a range of Gram positive and negative bacteria. Several genes identified from the genome of P. aeruginosa UWI-1 were postulated to contribute to the biosynthesis of these compounds and we attempted to outline a possible route for bacterial synthesis. This study demonstrated the extended metabolic capability of Pseudomonas aeruginosa in synthesizing new chemotypes of bioactive compounds.