'Unnatural' natural products a source of new drugs
polyketides - structures which form the backbone of a number of
drugs for cancer and infectious diseases - that could provide a new
route to the design of new medicines.
Polyketides are made in bacteria and fungi by the stepwise building of long carbon chains - two atoms at a time - by multifunctional enzymes called polyketide synthases. The antibiotics erythromycin and tetracycline and anti-tumour agents doxorubicin and epothilone all come from this class, which is second only to the penicillins in terms of their importance as naturally-derived medicines.
Although microorganisms generate polyketides with a variety of characteristics, one goal of drug discovery research is to increase this diversity even further to create a larger pool of polyketides promises more drugs with enhanced pharmacological properties.
Early attempts at creating artificial polyketides focused on altering the functional characteristics of naturally occurring polyketides, such as the length of the chain, the building blocks, and the patterns of the branches. This has been met with some success but has been limited by the range of structures available.
The solution, according to the authors of the latest study, is to change the starting unit from which the polyketide is generated. This is usually an acetate molecule, but Chaitan Khosla and colleagues have taken the process a step further by engineering bacteria to use an alternative, nonacetate primer molecule.
This has important practical implications because some medicinally significant compounds do not use the usual acetate primer unit. By dissecting out the specificities of the 'starter' and 'elongation' PKS enzymes and by mixing and matching modules, they have produced novel polyketide analogues (in this case, of anthraquinone) with more effective medically relevant properties.
One of the compounds they engineered shows enhanced efficacy in blocking the growth of breast cancer cells that depend on the activity of the oestrogen receptor, while a second polyketide inhibits an enzyme linked to adult-onset diabetes, demonstrating just two possible new therapeutic applications for synthesized polyketides. But, as the authors propose, this method promises to reveal new pharmaceutical agents that have not even been discovered yet.
The research is published in the February issue of the Public Library of Sciences' PloS Biology journal.
