ABSTRACT
Mycobacterium tuberculosis (Mtb) infection is among top ten causes of death worldwide, and the number of drug-resistant strains is increasing. The direct interception of human immune signaling molecules by Mtb remains elusive, limiting drug discovery. Oxysterols and secosteroids regulate both innate and adaptive immune responses. Here we report a functional, structural, and bioinformatics study of Mtb enzymes initiating cholesterol catabolism and demonstrated their interrelation with human immunity. We show that these enzymes metabolize human immune oxysterol messengers. Rv2266 - the most potent among them - can also metabolize vitamin D3 (VD3) derivatives. High-resolution structures show common patterns of sterols binding and reveal a site for oxidative attack during catalysis. Finally, we designed a compound that binds and inhibits three studied proteins. The compound shows activity against Mtb H37Rv residing in macrophages. Our findings contribute to molecular understanding of suppression of immunity and suggest that Mtb has its own transformation system resembling the human phase I drug-metabolizing system.
Subject(s)
Energy Metabolism , Host-Pathogen Interactions , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Tuberculosis/metabolism , 3-Hydroxysteroid Dehydrogenases/chemistry , 3-Hydroxysteroid Dehydrogenases/metabolism , Catalysis , Cytochrome P-450 Enzyme System/chemistry , Cytochrome P-450 Enzyme System/metabolism , Enzyme Activation , Host-Pathogen Interactions/immunology , Humans , Immunity , Isoenzymes , Models, Molecular , Oxysterols/chemistry , Oxysterols/metabolism , Recombinant Proteins , Structure-Activity Relationship , Tuberculosis/microbiologyABSTRACT
A series of novel phenolic antioxidants of amphiphilic structure has been synthesized. Investigations into the influence of aliphatic spacer length and nature of a hydrophilic anchor on the antioxidant activity allowed elucidating certain structure requirements for the membrane-addressed antioxidant designing.
Subject(s)
Alkanes/chemistry , Alkanes/pharmacology , Antioxidants/chemistry , Antioxidants/pharmacology , Molecular Structure , Structure-Activity RelationshipABSTRACT
Based on the membrane addressing concept, designing and synthesis of 11-(3,5-di-tert-butyl-2-hydroxyphenylcarbamoyl)undecanoic acid have been carried out. Antioxidant properties of the prepared compound were investigated in comparison with its non-amphiphilic analogues.