RESUMEN
Natural products serve as a great reservoir for chemical diversity and are the greatest source for antibacterial agents. Recent discoveries of platensimycin and platencin as inhibitors of bacterial fatty acid biosynthesis enzymes supplied new chemical scaffolds for potential antibacterial agents to overcome resistant pathogens. Discovery of natural congeners augment chemical modification in understanding of structure-activity relationship (SAR). Chemical and biological screening of the extracts led to isolation of three hydroxylated analogs of platencin. The C-12, C-14 and C-15 hydroxylated analogs showed attenuated activities which provided significant understanding of functional tolerance in the diterpenoid portion of the molecule. A truncated and oxidized C-13 natural congener was isolated which suggested direct intermediacy of ent-copalyl diphosphate for the biosynthesis of platensimycins and platencins.
Asunto(s)
Adamantano/análogos & derivados , Aminobenzoatos/química , Aminofenoles/química , Antibacterianos/química , Compuestos Policíclicos/química , Streptomyces/química , Adamantano/química , Adamantano/farmacología , Aminobenzoatos/farmacología , Aminofenoles/farmacología , Antibacterianos/farmacología , Cromatografía Líquida de Alta Presión , Fermentación , Haemophilus influenzae/efectos de los fármacos , Hidroxilación , Indicadores y Reactivos , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Compuestos Policíclicos/farmacología , Espectrofotometría Ultravioleta , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Thiazolyl peptides are a class of rigid macrocyclic compounds richly populated with thiazole rings. They are highly potent antibiotics but none have been advanced to clinic due to poor aqueous solubility. Recent progress in this field prompted a reinvestigation leading to the isolation of a new thiazolyl peptide, thiazomycin, a congener of nocathiacins. Thiazomycin possesses an oxazolidine ring as part of the amino-sugar moiety in contrast to the dimethyl amino group present in nocathiacin I. The presence of the oxazolidine ring provides additional opportunities for chemical modifications that are not possible with other nocathiacins. Thiazomycin is extremely potent against Gram-positive bacteria both in vitro and in vivo. The titer of thiazomycin in the fermentation broth was very low compared to the nocathiacins I and III. The lower titer together with its sandwiched order of elution presented significant challenges in large scale purification of thiazomycin. This problem was resolved by the development of an innovative preferential protonation based one- and/or two-step chromatographic method, which was used for pilot plant scale purifications of thiazomycin. The isolation and structure elucidation of thiazomycin is herein described.