Sir Alexander Fleming's 1928 discovery of penicillin, the product of a mold that he unintentionally cultivated on a Petri dish, revolutionized medicine. However, Fleming's famous mold, Penicillium notatum, didn't make much of the antibiotic, and industry turned to alternate strains to ramp up production. A new report shows that a single enzymatic mutation made all the difference.
Scientists employed P. notatum during early attempts to manufacture penicillin, but they later abandoned it favor of a more promising species of mold, P. chrysogenum, discovered on a cantaloupe in 1943. Another half-century of genetic tweaking has given rise to today's industrial strains of P. chrysogenum, which crank out roughly 1000-fold more penicillin than P. notatum.
To understand the reasons behind the improvement, José Luis Barredo and colleagues at Antibióticos, a pharmaceutical company in Leon, Spain, analyzed the biochemistry of both strains.
The key difference was how the strains metabolize phenylacetic acid (PA), a precursor of penicillin. Mold can convert PA into either penicillin or 2-hydroxy-PA, a product formed by the enzyme expressed from a gene called pahA . Both P. chrysogenum and P. notatum contain pahA , but a single base pair change in P. chrysogenum 's gene renders the enzyme less active. As a result, the industrial sweetheart converts much more PA to penicillin. Expressing the P. notatum version of pahA in a modern P. chrysogenum strain dramatically squelched its production of penicillin, report the researchers online this month in the journal Fungal Genetics and Biology, confirming that pahA is a key determinant of penicillin yield.
"It is quite remarkable that this great difference in enzyme activity and penicillin production ability is due to an extremely minor difference in the genes encoding the enzyme," says microbial biochemist Arnold Demain of Drew University in Madison, New Jersey. Before making this discovery, Barredo's team had considered knocking out pahA in an effort to boost antibiotic production in industrial strains. Since nature has already done this work for them, they must now seek other strategies.