Novel FK506 and FK520 analogues via mutasynthesis: mutasynthon scope and product characteristicsElectronic supplementary information (ESI) available: Materials and methods for generating strains and experimental data for compounds assayed, materials and methods for in vitro and in vivo assays. See DOI: 10.1039/c2md20266b

Novel FK506 and FK520 analogues were generated via biosynthetic engineering in order to generate analogue compounds with equal potency but improved pharmacological profiles compared to FK506. Strains suitable for mutasynthesis were produced by abolishing the activity of the rapK homolog fkbO , thereby disabling starter unit biosynthesis, and by replacing the polyketide synthase loading modules with the AT-ACP didomain equivalent from the avermectin PKS. A test set of FK506 and FK520 analogues was prepared and assessed for potency, physicochemical properties and pharmacokinetics, revealing that these compounds retain potency but are otherwise differentiated from the parent compounds. Novel FK506 and FK520 analogues were generated via biosynthetic engineering in order to generate analogue compounds with equal potency but improved pharmacological profiles compared to FK506.