US scientists have revealed the genes that lead to an antitumor antibiotic. The team, led by Ben Shen at the University of Wisconsin-Madison, says the research could provide the tools to create new anticancer drugs.

'The idea is to use metabolic pathway engineering to make new analogues of zorbamycin, a member of the bleomycin family of antitumor antibiotics,' explains Shen. Modifying bleomycin's biosynthesis to create novel analogues has proved difficult as the organisms that produce it are not amenable to genetic manipulation. Now Shen and his team have identified the gene cluster responsible for synthesising zorbamycin - another glycopeptide antitumor antibiotic - in a different bacterium that is easier to manipulate. 

Modifying the gene cluster responsible for zorbamycin could lead to bioactive analogues

Shen explains that knowledge of the zorbamycin gene cluster will 'allow us now to explore the potential of the zorbamycin scaffold'. The aim is to create new compounds by combinatorial biosynthesis methods. By analysing the antibiotic gene cluster his team showed that while the genetic code of the zorbamycin gene cluster contains 40 open reading frames - stretches of the genome that could encode a protein - only 22 of these were homologous to those found for bleomycin. 'Homologous parts of the biosynthetic machinery highlight their structural similarities, while the differences account for their structural variations, thereby providing opportunities to engineer novel analogues,' explains Shen. 

But the new knowledge could have implications beyond new zorbamycin analogues - it could be exploited to prepare analogues on a larger scale. 'Bleomycin is an important anticancer agent that is used clinically for treatment of testicular cancer - the disease that cyclist Lance Armstrong recovered from,' comments Timothy Bugg, professor of biological chemistry at the University of Warwick, UK. 'But its large scale production is hampered by the yield of the natural product from the producing organism,' he explains. 'The isolation of further strains of Streptomyces able to produce compounds in this class offers the possibility of improving the yield of natural product by genetic manipulation, an application of biotechnology that could literally save lives in the clinic.' 

Russell Johnson

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