Doramectin

By disabling the primary metabolic pathways leading to the native starter units, the inherent promiscuity of the Ave loading module was also used to generate a number of avermectin derivatives in S. avermitilis. The most effective antiparastic among them, doramectin (Dectomax), incorporates a cyclohexane carboxylic acid (CHC) as starter unit. It is, in fact, a showcase for polyketide pathway engineering, as it is the first drug to be derived from this approach, and is now one of the most successful veterinary anthelmintics. Recently, an attempt was made to engineer an alternative doramectin producer (Fig. 14) by exchanging the Ave loading module with that from the phoslactomycin PKS133 whose native substrate is CHC-CoA, coupled with introduction of a CHC-CoA biosynthetic pathway. The resulting strain did yield doramectin in amounts higher than that derived from supplementing the wild type strain with CHC (53 vs. 9mg L^-1), but which were overall significantly reduced relative to avermectin production from the parent (500 mg L^-1) – and native avermectin was also produced. Thus this system will require further improvements in order to be suitable for industrial-scale production of doramectin.