Everybody is familiar, at least in passing, with classical strain improvement. You treat cells with a chemical or physical mutagen, kill off most in the process, and screen the survivors for that rare clone which produces more of the product you are interested in. This new strain becomes the starting point for a new round and you repeat the process. It is a bit more involved than that but you get the idea. You never really know why the strain is improved – unless you sequence the thing – but if you are in industry your job is to become rich (because you made more product cheaper) and not famous (because you published a paper).
In the era of metabolic engineering where scientists wanted to be more targeted in the way they improved the productivity of strains, classical strain improvement got the reputation of being too slow and too labor intensive for the improvements that were achieved. That might have been true 20 years ago but with the use of miniaturized cultivation along with automated colony picking and liquid handling; a large number of colonies can be screened regardless of whether their genetic variability was introduced by metabolic engineering or chemical mutagenesis.
Some companies have never forgotten the value of classical strain improvement. A paper given at the 2009 Recent Advances in Fermentation Technology Meeting (RAFT) described how Eli Lilly has used this approach for over fifty years to continually improve strains for in-line natural products. I saw the same thing at Merck for the continual improvement of avermectin and lovastatin producing strains.
It has been pleasantly surprising to see biology companies producing biofuels and renewable chemicals use classical strain improvement as a supplement to synthetic biology or other metabolic engineering approaches. Amyris is one such company to employ this approach as described in a paper given at the 2010 SIM annual meeting (oh, and by the way, didn’t they just have an IPO?). It may not be sexy but it is effective, efficient, and a great tool to have in the tool box.
About Neal Connors
Dr. Neal Connors is currently the owner/president of Phoenix BioConsulting, LLC (www.phoenixbioconsulting.com); a company providing consulting services to the fermentation, industrial microbiology, biotechnology, and legal sectors.
Bacteria which infect people with cystic fibrosis could help combat other antibiotic-resistant microbes, according to a team from Cardiff and Warwick Universities.
Continuous use of existing antibiotics means that resistant bacteria are now causing major health problems all over the world. New antibiotics are urgently needed to combat the emergence of multidrug-resistant bacteria such as the MRSA superbug.
Now a surprising source of hope has emerged in the form of Burkholderia, a group of bacteria which can cause severe lung infections in people with the genetic disorder cystic fibrosis. However, the Cardiff and Warwick team has now discovered antibiotics from Burkholderia are effective against MRSA and even other cystic fibrosis infecting bacteria.
Dr Eshwar Mahenthiralingam, of Cardiff University’s School of Biosciences, has been studying Burkholderia for the last decade. Using forensic fingerprinting tests to genetically identify the bacteria, Dr Mahenthiralingam’s research group has tracked strains all over the world and helped develop guidelines to prevent it spreading.
By the summer of 2007, Dr Mahenthiralingam had built up a large collection of Burkholderia bacteria. He and his team then decided to screen them for antibiotics active against other bacteria, particularly drugs with the potential to kill other bacteria that infect cystic fibrosis patients. Over the next two years, Dr Mahenthiralingam’s team discovered that around one quarter of Burkholderia bacteria have very strong antibiotic activity on multidrug-resistant pathogens such as MRSA. One particular strain, Burkholderia ambifaria, was found to produce two very potent antibiotics active on resistant bacteria, in particular Acinetobacter baumanii.
The chemical structures of the antibiotics, called enacyloxins, were determined by Professor Gregory Challis and Dr. Lijiang Song at the University of Warwick, demonstrating that they belong to one of the most successful families of natural product drugs, the polyketides. Other examples of polyketides include erythromycin, which is used to cure many bacterial infections, and doxorubicin, used as an anti-cancer drug. Professor Challis commented: “The combination of enzymes used by Burkholderia to make the enacyloxins is very unusual. Our insights into this process should allow us to use cutting edge synthetic biology techniques to produce novel enacyloxin analogues with improved pharmaceutical properties.”
The team’s findings have now been published in the journal Chemistry and Biology. Dr Mahenthiralingam commented: “Burkholderia are soil bacteria like Streptomyces, which are the source of most of our current antibiotics. Our research therefore offers real hope of a completely new source for the identification and engineering of highly potent antibiotics. With antibiotic resistant bacteria causing great suffering around the world, these new sources are urgently needed.”
Professor of Chemical Biology
Department of Chemistry
University of Warwick
8/17/11 Recent Publications in JIMB
I would like to bring to your attention three recent publications in Journal of Industrial Microbiology and Biotechnology (JIMB) and one by JIMB Senior Editor Erick Vandamme in another report that I believe will be of interest to a broad spectrum of SIM members, JIMB readers and the industrial microbiology/biotechnology community in general. The first two are recent reviews published in JIMB dealing with our old friends the actinomycetes, their manipulation for strain improvement and natural products. The third is a review on current uses of continuous culture techniques. The fourth is a major “Position Paper” on biomass and its uses recently published by the Belgian Royal Academy of Science and the Arts , Class of Technical Sciences. These reports are all “state of the art”; I think you will enjoy all four.
The first review is, “Current approaches to exploit actinomycetes as a source of novel natural products” by O. Genilloud, I. Gonzalez, O. Salazar, J. Martin, J.R. Tormo and F. Vicente. J Ind Microbiol Biotechnol (2011) 38#3: 375-389.
The second review is, “Strain improvement in actinomycetes in the postgenomic era” by Senior Editor Richard H. Baltz. J Ind Microbiol Biotechnol (2011) 38#6:657-666.
The third review is, “The renaissance of continuous culture in the post-genomic age” by Senior Editor Alan T. Bull. J Ind Microbiol Biotechnol (2010) 37#10:993-1021.
The fourth paper by Erick J. Vandamme, Chief Author and Editor, is a major “Position paper ” on biomass and its uses recently published by the Belgian Royal Academy of Science and the Arts , Class of Technical Sciences, BACAS, ( www.kvab.be ), titled ” Industrial Biomass: Source of Chemicals, Materials and Energy !”. Vandamme, Erick J., T. Anthonis, S. Dobbelaere, et al., February 2011, p.40: KVAB D/2011/0455/02 ISBN 978906569077 http://www.kvab.be/standpunten.aspx. Although this report is Euro-centric it should be of great interest to all working in the areas of renewable fuels and chemicals. Erick Vandamme is also a Senior Editor for JIMB.
Robert (Bob) D. Schwartz
On August 16th, the Office of Energy Efficiency and Renewable Energy (EERE) at the U.S. Department of Energy reports that President Obama has announced up to $510 million will be invested, with private sector partnership, during the next three years into biofuels. Excerpt from EERE progress alert:
President Obama Announces Major Initiative to Spur Biofuels Industry and Enhance America’s Energy Security
President Obama today announced that the U.S. Departments of Agriculture, Energy, and Navy will invest up to $510 million during the next three years in partnership with the private sector to produce advanced drop-in aviation and marine biofuels to power military and commercial transportation. The initiative responds to a directive from President Obama issued in March as part of his Blueprint for A Secure Energy Future, the administration’s framework for reducing dependence on foreign oil. The biofuels initiative is being steered by the White House Biofuels Interagency Work Group and Rural Council, both of which are enabling greater cross-agency collaboration to strengthen rural America.
As discussed at previous Board of Directors and Senior Editors meetings, in August 2010 our citation index had fallen to an IF of 1.798 and we were listed as 81/150. In 2009 we were at 1.919 and 72/144. To remedy this problem the Senior Editors:
- • endorsed adding more reviews, particularly mini-reviews (done, mainly through the efforts of Dick Baltz, JIMB Reviews Editor);
- • expanded our Senior Editor Board (we added four and now have 13 Senior Editors, representing seven countries, with expertise in areas where we were lacking and we are more international in structure);
- • expanded our Editorial Board (we now have 86 members; members are more likely to submit their work to JIMB and provide more expert reviewers).
As a result of these efforts, the JIMB IF for 2010 has risen to 2.416 and we are number 63/164 journals. This represents 4326 citations. Perhaps more interesting, we are 63/164 —>38.4% of the top journals in our group. In 2009 we were 81/150 or 54% and in 2008, 72/144 or 50%. We are moving in the right direction and will continue to do so!
Summarizing the first six months of 2011 we processed 421 manuscripts, three of which came from 33rd Symposium on Fuels and Chemicals. This compares to 456 for the first six months of 2010, 44 of which came from the 32nd Symposium on Fuels and Chemicals. Thus, manuscript flow is similar to 2010. For 2011, of the 421 manuscripts action (accept, revise or reject) has been taken on 391: 59 (15.1%) have been accepted or are in revision; 332 (84.9%) have been rejected. Our rejection rate for 2010 was about 75%. Again, we continue to move in the right direction as the quality of published manuscripts and reviews continue to improve.
Robert (Bob) D. Schwartz
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