If rifamycin binds the polymerase after the chain extension process has started, no inhibition is observed on the biosynthesis, consistent with a steric-occlusion mechanism. Single step high level resistance to the rifamycins occurs as the result of a single amino acid change in the bacterial DNA dependent RNA polymerase. Biosynthesis The first information on the biosynthesis of the rifamycins came from studies using the stable isotope Carbon-13 and NMR spectroscopy to establish the origin of the carbon skeleton. These studies showed that the ansa chain was derived from acetate and propionate, in common with other polyketide antibiotics. The naphthalenic chromophore was shown to derive from a propionate unit coupled with a seven carbon amino moiety of unknown origin. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-hydroxybenzoic acid (AHBA), via type I polyketide pathway (PKS I) in which chain extension is performed using 2 acetate and 8 propionate units. AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism. This is due to the observation that 3 amino-acid analogues converted into AHBA in cell-free extracts of A. mediterranei. The rif cluster is responsible for the biosynthesis of rifamycins. It contains genes through , which were shown to biosynthesize AHBA.[10] , , , and are believed to act as transaminases in order to form the AHBA precursor kanosamine. "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and phosphoenolpyruvate. through encode a type I polyketide synthase module, with the loading module being a non-ribosomal peptide synthetase. In all, assemble a linear undecaketide and are followed by , which encodes an amide synthase and causes the undecaketide to release and form a macrolactam structure. Moreover, the rif cluster contains various regulatory proteins and glycosylating genes that appear to be silent. Other types of genes seem to perform post-synthase modifications of the original polyketide. Derivatives Lepetit introduced Rifampicin, an orally active rifamycin, in 1966. Rifabutin, a derivative of rifamycin S, was invented by Italian drug manufacturer Achifar in 1975 and came onto the US market in 1992. Hoechst Marion Roussel (now part of Aventis) introduced rifapentine to the US market in 1998, with Achifar having synthesized it in 1965. Use of rifapentine remains uncommon as a treatment for pulmonary tuberculosis, and treatment with rifapentine is given on the basis of careful selection of patients. Rifaximin is an oral rifamycin