"One of the daunting challenges is to rapidly inventory the tens to hundreds of thousands of molecules the bacteria construct to live, and then to read this inventory to understand how the bacteria compensate for their changing circumstances. To complicate matters further, we are looking for new drug-like molecules, so by definition we are looking for something that has not been seen before," said McLean.
Working with Research Assistant Dagmara Derewacz and graduate students Cody Goodwin and Ruth McNees, Bachmann and McLean started with the well-characterized soil bacterium Nocardiopsis. They exposed the bacterium to two different antibiotics streptomycin and rifampicin and observed the results.
"The first thing that happens is almost all of the bacteria die. Less than one cell in a million survives," said Bachmann.
The chemists then cultured the survivors (six streptomycin-resistant strains and five rifampicin-resistant strains) without the antibiotic and used McLean's instrumental methods to profile the drug-like compounds that they produced.
They discovered that the differences were much greater than they expected. The survivors had undergone extensive mutations, not only in the genes that produce secondary metabolites but also in the housekeeping genes that alter the way they make RNA and proteins. As a result, they determined that the resistant strains produced more than 300 compounds that were not expressed by the original organism.
"The cells appear to be 'de-repressing' as many of their silent genes as possible. This seems
|Contact: David Salisbury|