Correlation of structure and activity in ansamycins: structure, conformation, and interactions of antibiotic rifamycin S.

The crystal and molecular structure of the DNA-dependent RNA polymerase inhibiting antibiotic rifamycin S (C37H45O12N) as a dihydrate has been determined, and the conformation necessary for activity has been correlated with those of other active rifamycins. The orthorhombic unit cell, space group P212121 with dimensions of a = 13.010 (2), b = 14.236 (2), c = 20.571 (4) A, contains 4 molecules. The structure was solved by a combination of vector search and direct methods and refined anisotropically to an R factor of 0.048 for 2855 reflections. The conformation of the ansa chain differs from those of rifampicin and rifamycin B but resembles that of rifamycin SV at the joining points, C(2) and C(12), of the ansa chain to the naphthoquinone chromophore. The middle part of the ansa chain, which is essential for its activity against the enzyme, has the same conformation as other active rifamycins. The effect of the 3-substitution on the ansa chain conformation is that the carboxyl (C(15) = O) group wings around the N-C(16) direction, depending upon the electronegativity of the 3-substituent. The hydrogen bonding involves O(1), O(2), O(8), O(9), O(10), and the water molecules. A possible four-stage model for the interaction of the rifamycins with the enzyme DNA-dependent RNA polymerase has been speculated.