RESUMEN
Based on high-resolution tandem mass spectrometry (HR-MS2) and global natural products social molecular networking (GNPS), we found that plant-derived daidzein and genistein derivatives are polyhalogenated by termite-associated Actinomadura species RB99. MS-guided purification from extracts of bacteria grown under optimized conditions led to the isolation of eight polychlorinated isoflavones, including six unreported derivatives, and seven novel polybrominated derivatives, two of which showed antimicrobial activity.
Asunto(s)
Actinomadura/química , Antibacterianos/química , Isoflavonas/química , Isópteros/microbiología , Animales , Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Genisteína/química , Genisteína/farmacología , Halogenación , Isoflavonas/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Redes y Vías Metabólicas , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
A synthesis program for structurally complex macrocycles is very challenging. Herein, we propose a biosynthesis pathway of the pyranylated cyclodepsipeptide verucopeptin to make enough supply and to diversify verucopeptin by genetic manipulation and one-step semisynthesis. The synthesis relies on the intrinsic reactivity of the interchangeable hemiketal pyrane and opened keto along with adjacent alkene. Biological evaluation of verucopeptin-oriented analogs delivers a potent AMP-activated protein kinase (AMPK) agonist, antibacterial agent, and selective NFκB modulator.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Antibacterianos/farmacología , Depsipéptidos/farmacología , FN-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Staphylococcus aureus/efectos de los fármacos , Actinomadura/química , Antibacterianos/biosíntesis , Antibacterianos/química , Depsipéptidos/biosíntesis , Depsipéptidos/química , Células HEK293 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , FN-kappa B/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Growth from spores activated a biosynthetic gene cluster in Actinomadura sp. RB29, resulting in the identification of two novel groups of halogenated polyketide natural products, named maduralactomycins and actinospirols. The unique tetracyclic and spirocyclic structures were assigned based on a combination of NMR analysis, chemoinformatic calculations, X-ray crystallography, and 13C labeling studies. On the basis of HRMS2 data, genome mining, and gene expression studies, we propose an underlying noncanonical angucycline biosynthesis and extensive post-polyketide synthase (PKS) oxidative modifications.
