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A team of researchers at the University of Wisconsin-Madison (my alma mater) genetically engineered a strain of Streptomyces platensis to overproduce the antibiotics platensimycin and platencin. They accomplished this by deleting a regulatory gene (ptmR1, whichencodes a putative GntR-like transcriptional regulator) in the antibiotic synthetic pathway that controls production. The newly engineered strain has been reported to overproduce platensimycin and platencin with yieldsof 323 ± 29 mg/L and 255 ± 30 mg/L, respectively. This represents a 100-fold increase in the yields observed with corresponding S. platensis wild type strains.

Platensimycin is the first of a new class of natural product antibiotics (with a novel mode of action) to be discovered in the past 40 years.  It exhibits strong, broad-spectrum Gram-positive antibacterial activity by selectively inhibiting cellular lipid biosynthesis. Treatment with platensimycin eradicates Staphylococcus aureus infection in mice. Because of its unique mode of action, platensimycin shows no cross-resistance to other key antibiotic-resistant strains tested, including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and vancomycin-resistant enterococci.

Platencin, also a natural product, is chemically and biologically related but different from platensimycin. Like platensimycin, it exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. And, it doesn’t exhibit cross-resistance to methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant Enterococci. Moreover, platencin shows potent in vivo efficacy without any observed toxicity.

Both antibiotics show promise for commercialization. While we need new antibiotics, both platensimycin and platencin target only Gram positive bacteria. Infections caused by multiple drug resistant Gram negative bacteria are threatening to overtake those caused by Gram positive in the very near future. At present, to the best of my knowledge, there are no new antibiotics in the pipeline directed against multiple drug resistant Gram negative strains.

Until next time...

Good Luck and Good Antibiotic Hunting!!!!!!!!

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New Jersey-based Pharmacopeia, the first-ever combinatorial chemistry company, announced that it had agreed to be purchased by Ligand Pharmaceuticals in a stock deal worth about $70 million. Onetime a leader in combinatorial chemistry and high throughput screening, Pharmacopeia has struggled of late after it jettisoned its profitable molecular modeling division several years ago. While the company was able to advance several of its lead compounds into early phase clinical testing, its  longtime business model, predicated on multiple, small discovery deals with large pharmaceutical companies, was unable to provide enough capital to continue to sustain operations.

Pharmacopeia was established in 1993 after its founders licensed from Columbia University several of the first issued combinatorial chemistry patents. The company was a pioneer in combinatorial chemistry (and subsequently high throughput screening) and was the first to publicly tout the virtues of combinatorial chemistry in drug discovery. By the mid-1990s, many pharmaceutical companies had embraced combinatorial chemistry as the “next big thing” and began eliminating traditional natural product and medicinal chemistry jobs. The industry’s love affair with combinatorial chemistry grew so strong that many companies (most notably Merck), completely eliminated their natural products discovery departments in the late 1990s. Unfortunately, the role of combinatorial chemistry in drug discovery never lived up to its promised potential and was largely abandoned in the early 2000s. Although combinatorial chemistry is now part of the modern day drug discovery paradigm, this onetime “shining star” has largely been relegated to a minor supporting role.

I first became acquainted with Pharmacopeia in 1994 after I took a job with Transcell Technologies, a now-defunct biotechnology company that was co-located with Pharmacopeia in a research facility in Monmouth Junction, NJ. While Transcell and Pharmacopeia shared a cafeteria and some common laboratory equipment, Pharmacopeia employees were strictly forbidden to talk with Transcell employees— lest they inadvertently divulge proprietary combinatorial chemistry concepts that might jeopardize the company’s future. Coincidentally, a guy who lived two doors down from my family and me turned out to be Pharmacopeia’s in-house intellectual property attorney. Although, Ron and I became good friends, he was also extremely tight-lipped about the “goings-on” at Pharmacopeia. Privately-held Pharmacopeia went public in 1995 and at one time, its market capitalization was almost $1.0 billion.

By any reckoning, a 15-year run is outstanding for a biopharmaceutical company. However, as the old adage goes, “All good things must come to an end.” At present, it is not clear, whether or not California-based Ligand will relocate the company or cut jobs. Nevertheless, Pharmacopeia’s impending demise sends a clear signal that the golden age of combinatorial chemistry has ended!

Until next time….

Good Luck and Good Job Hunting!!!

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Merck announced last week that it will cut 1,200 sales jobs in the U.S. by the end of July. The company also confirmed a plan to eliminate a small natural products group in Spain and Rahway, NJ. Whereas the salespeople who lost their jobs were given notice by the company, the natural products researchers in Spain (and Rahway) learned of their imminent demise via a power point presentation given by a Merck executive (whose name has not been disclosed).

According to reports, the Merck executive inadvertently included a slide in his presentation that outlined the plan for the layoffs to an audience that included Merck employees. Oops… The decision to close down in-house natural products research will impact approximately 50 researchers in Spain and "a significantly smaller number" in Rahway, N.J., according to Merck spokesman.

Merck eliminated most of its natural products discovery programs about 10 years ago but apparently maintained a small group hoping for a natural products discovery comeback. I, along with others, think that the blockbuster drugs of the future will come from natural product discovery. For those doubters out there, would somebody care to tell me the names of any blockbuster drugs that were discovered by combinatorial and computational chemistry?

I rest my case! 

Thanks to Ed over at Pharmalot for the heads up on this story!!!!!

Until next time…

Good Luck and Good Job Hunting!!!!!!!!!!!!

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I happened upon a Sunday morning talk show yesterday where one of the guests was discussing strategies that employees ought to adopt to keep their jobs in a recessionary economy. For those of you who haven’t been paying attention, the US economy lost 63,000 jobs last month; another bit of evidence that we are sliding into an unavoidable recession. 

The talk show guest posited that only those employees who were able to quickly adapt to rapidly changing corporate/business environments would keep their jobs; the other less adaptable employees would find themselves jobless. Call me crazy, but his analysis sounded eerily similar to Darwin’s principle of natural selection or “survival of the fittest”–only those members of a population who were able to adapt (through mutations in Darwin’s case)  to changing environmental conditions will survive; the other less adaptable members will perish. Imagine that, using a recessionary economy to illustrate one of the fundamental principles of Darwin’s theory of evolution–how cool is that?

Here are some insights into how to keep your job during a recession when many companies are unstable and in flux. First, employees who work at financially-troubled companies must embrace the changes frequently instituted by management whether or not they agree with them. Invariably, there will be a cadre of employees who openly and publicly criticize the “new corporate policies”–these will likely be the employees who are demoted or “right-sized” out of the company.  In Darwinian terms, these employees are unable to adapt to change and they will either be eliminated or their standing in the population (company) will be diminished.  On the other hand, the employees who are able to embrace change will not lose their jobs and will likely be able to maintain or improve their standing in the population (company).  In other words, adaptable employees have a selective, competitive advantage over unadaptable ones which will allow them to survive and flourish in their new environment. Second, it is probably not wise during periods of corporate upheaval, for mid-level managers or employees to tout their past accomplishments or remind management about their worth to the company. In times of change, management embraces individuals with forward-looking ideas (to facilitate change) not those who are rooted in the past and are invested in antiquated corporate policies and practices. Again, only those employees who adapt will be able to survive and compete in their new corporate environment.  Finally, as a science educator, it is always exhilarating and exciting to find new ways to teach Darwin’s Theory (sic) of Evolution so that it makes sense to lay audiences. Maybe watching Sunday morning talk shows isn’t a waste of time after all!!!!

Until next time… 

Good Luck and Good Job Hunting (adapt)!!!!!!!!!

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