EMBARGOED UNTIL: Monday 5/20, 3 PM MDT
(Symposium Session 141)
Harvard Medical School
Boston, MA, United States
Bacteria from the soil called ‘actinomycetes’ are the deepest natural source of useful medicinal compounds, including antibiotics, antifungals, and anticancer agents. We have found that when two species of these bacteria grow near each other, they make many more chemical compounds than they do when they grow alone. This finding is significant because it suggests that by growing these bacteria together, we may gain access to a much broader range of new compounds from these bacteria.
Microbiologists Matthew Traxler and Roberto Kolter of Harvard Medical School designed the experiments that led to these findings. They teamed together with UCSD chemist Pieter Dorrestein and members from his lab, Jeramie Watrous and Theodore Alexandrov. The Dorrestein lab specializes in developing new tools that allow for comprehensive chemical mapping of biological samples. Matthew Traxler made several research trips to UCSD, and together with Jeramie Watrous, conducted deep chemical sampling of colonies of actinomycetes growing alone or in pairs. The complex chemical datasets were analyzed by Matthew Traxler and Jeramie Watrous using software developed by Theodore Alexandrov. This work was funded by the National Institutes of Health (Postdoctoral Fellowship 5F32GM089044-02 to MFT, grant GM82137 to RK, and grants GM094802 and AI095125 to PCD. TA was also supported by the European Union 7th Framework Programme (grant 305259). This work is to be presented at the American Society for Microbiology General Meeting held in Denver, Cololorado on Monday May 20, 2013.
New antibiotics will be needed in the future as resistance to commonly used drugs continues to spread among human pathogens. Actinomycete bacteria produce more than 60% of all anitbiotics used in clinical settings, and the compounds an individual actinomycete can make are determined by its genes. When the first actinomycete genomes were sequenced, scientists were surprised to find that each actinomycete has genes to make many more compounds than previously thought. This is because under normal laboratory conditions, the overwhelming majority of genes for compound production are not active. We wondered if growing two species of these bacteria together would stimulate them to produce more of these interesting compounds. To see if this might be the case, we grew the model actinomycete, Streptomyces coelicolor next to another actinomycete (Streptomyces viridochromogenes, shown in the picture below). After a week of growth, it was clear that the other actinomycete stimulated Streptomyces coelicolor to make a red pigmented antibiotic called prodigiosin. We repeated the same experiment, each time pairing the Streptomyces coelicolor with one of five different actinomycetes. These interactions stimulated different amounts of pigment production in Streptomyces coelicolor.
We next studied these interactions using two new chemical techniques called nanoDESI (Nano-scale desorption electrospray ionization) Mass Spectrometry and MALDI-TOF (Matrix-assisted laser desorption/ionization time-of-flight) Imaging Mass Spectrometry. These techniques allowed us to extensively examine the chemicals made by the Streptomyces coelicolor during each interaction. Overall, the Streptomyces coelicolor made greater than >250 compounds in the 5 different interactions, and the set of compounds it made was different depending on the interacting partner. Using newly developed software, we were able to see that many of these 250 compounds were structurally related to one another in multiple ‘chemical families’.
While we were working to sort through these chemical families to look for new compounds, we found one group of related chemicals that was readily identified. We found that Streptomyces coelicolor made at least 12 different versions of a molecule called desferrioxamine; and many of these versions have never been seen before. Desferrioxamine is a type of compound called a siderophore, which bacteria use to pick up iron from their environment. Desferrioxamine is used in medicine to treat patients who have an overload of iron in their bloodstream. While desferrioxamine itself is not an antibiotic, the identification of so many more new versions of this molecule in our experiments illustrates the potential of this approach for new compound discovery.
Bacteria are incredible chemists, capable of producing an wide array of useful compounds. By listening in on their intimate chemical conversations with the powerful chemical methods used here, we may be able to tap into an important new source of potentially useful chemical compounds.