title: Reverse Biosynthesis: Generating Combinatorial Pools of Drug Leads from Enzyme-Mediated Fragmentation of Natural Products.
abstract: A combinatorial pool of hydroxamic acid fragments as potential metalloprotein drug leads was generated from the enzymatic hydrolysis of the natural product desferrioxamine B (DFOB). DFOB is a metabolite produced by Streptomyces pilosus for iron acquisition, and can be selectively catabolised by Niveispirillum irakense to access carbon for growth. The supernatant of a DFOB-supplemented culture of N. irakense was analysed by LC-MS at intervals over 168 h. This identified a mixture of endo-hydroxamic acid fragments that contained reactive terminal groups. The supernatants from two cultures (at 48 h and 168 h) were reacted with 1,8-naphthalic anhydride in a microwave synthesiser to generate pools of scriptaid analogues, which were screened against ZnII-containing histone deacetylases (HDACs) and FeIII-containing 5-lipoxygenase (5-LO). Compound S2 showed relative potency against 5-LO (IC50=59 μm; BWA4C, 17 μm); it was 28-fold more selective towards 5-LO than HDAC1. Compound S1 inhibited HDAC1 but not 5-LO. Enzyme-mediated reverse biosynthesis could yield new benefits from structurally complex natural products in drug design.
authors.affiliation: School of Medical Sciences (Pharmacology), The University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Tomas
authors.identifier: 0000-0002-8925-9064
authors.initials: T
authors.lastname: Richardson-Sanchez
authors.affiliation: School of Medical Sciences (Pharmacology), The University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: William
authors.identifier: 0000-0002-7161-4152
authors.initials: W
authors.lastname: Tieu
authors.affiliation: School of Medical Sciences (Pharmacology), The University of Sydney, Camperdown, NSW, 2006, Australia.
authors.forename: Rachel
authors.identifier: 0000-0002-2703-883X
authors.initials: R
authors.lastname: Codd
mesh_terms: D001688:Biological Products / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D002853:Chromatography, Liquid; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery / Q000379:methods*; D057075:Enzyme Assays; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D001688:Biological Products
keywords: bacterial interspecies interactions; combinatorial drug discovery; inhibitors; natural products; reverse biosynthesis