The role of combichem in antibiotic discovery
The role of combichem in antibiotic discovery.
Turning to the second method of identifying new antibiotics—mining orphan secondary metabolic pathways— Khosla explained that his group has used whole-genome sequencing and other technologies to identify close to 900 distinct assembly-line polyketide synthases, of which fewer than 20 percent have well-characterized substrates and products. To his knowledge, there is no ongoing large-scale effort to mine this family of polyketide assembly lines despite the fact that more than a dozen commercially important antibiotics come from the 20 percent of assembly lines that are well characterized and that make known molecules. His group has been developing techniques for refactoring these assembly-line pathways in heterologous hosts to produce novel compounds from glucose and propionic acid. In one project using such a system, Khosla’s team and collaborators from Kosan Biosciences were able to produce commercial quantities of the anticancer agent epothilone D within three years after this compound’s discovery.
initiating a ‘New Age of Antibiotic Discovery’
Looking to the future, Khosla said that it will one day be possible to engineer these assembly lines to make entirely new molecules, the third approach to antibiotic discovery. His group and others have developed a number of methods of engineering assembly-line polyketide biosynthetic pathways, but more work is needed to truly realize the promise of this approach. The main challenge to address is conceptual rather than technical, he explained. “We do not yet understand fully how these assembly lines work, and we certainly do not yet understand the structural basis for the modularity of these assembly lines,” he said. “Until we do, it is premature to predict where this approach will take us.”