As more and more bacteria become resistant to first-line antibiotics, the development of new agents is becoming increasingly important. Now, new research, published in Science
, outlines how “commercial chemicals” found in researchers’ laboratories at Yale University can be used to synthesize “molecules related to the natural product pleuromutilin
This antibacterial is a fungal byproduct, the antibacterial qualities of which were first discovered in the 1950s. Through semisynthesis, researchers have been able to create thousands of derivatives of pleuromutilin. In addition, in the past decades, pleuromutilin was approved for treatment of “gram-positive bacterial skin infections,” according to the researchers. Nonetheless, many of the pleuromutilin derivatives “only vary at a single position in the molecule,” according to a press release
. However, fully synthesizing pleuromutilin would allow for the development of new antibiotic agents, and this is what the Yale researchers set out to do.
Seth Herzon, PhD, professor of chemistry at Yale University, and member of the Yale Cancer Center, explained that he first tried to tackle this issue in 2008. He said, “We worked on this project for a few years when I started at Yale, but didn’t record much success. The pharmaceutical industry has historically been the driving force behind antibiotics development. However, antibiotics are essentially at the bottom of the list in terms of investment return. Consequently, most major pharmaceuticals have walked away from this area.”
According to Joseph Larsen, PhD, Director of the Biomedical Advanced Research and Development Authority (BARDA) with the US Department of Health and Human Services, developing new antibiotic agents
can take years, and only become profitable after an average of about 23 years. In addition, in an interview
®, Robert W. Malone, MD, MS, CEO/CSO of Atheric Pharmaceuticals, LLC, mentioned that getting a new drug or vaccine on the market takes around $1 billion and approximately 10 years. However, there is less incentive in creating new antibiotics because of revenue. According to Dr. Larsen, “for the last 6 antibiotics approved in the United States, the projected first 2 years’ sales ranged between $30 million to $80 million, which is not much when compared to medications used to treat more chronic diseases, which routinely have first 2 years’ sales in excess of a billion dollars.”
In their most recent study, Dr. Herzon and his colleagues were able to “prepare an isomer of pleuromutilin – a compound that has the same connectivity, but with a different arrangement of atoms – and rearrange it in the final steps of the synthesis to pleuromutilin.” With this, the research group was able to fully synthesize pleuromutilin, which may allow for the development of more antibiotics. The group outlined their complete synthesis methods in their study.
The authors concluded, “We can envision adapting the strategy outlined herein to create additional derivatives with optimized structures (ring sizes, atomic substitution, and/or substitution patterns) that may further address constraints inherent to semisynthetic approaches and may be accessible by shorter, higher-yielding sequences. Recent successes in the development of convergent routes to tetracycline and macrolide antibiotics underscore the potential to generate new clinical antibacterial candidates by total synthesis.”
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