What is borrelidin?
Borrelidin is a naturally occurring antibiotic isolated from the Streptomyces species and initially from Streptomyces rochei in 1949. It is called Borrelidin because it was firstly discovered as having anti-Borrelia activity. Borrelia is a type of bacteria.
Please can you outline some of the compounds similar to borrelidin that have been used as treatments for microbial infections?
Streptomyces bacteria produce several clinically useful antibiotics including neomycin, cypemycin and bottromycin. Bottromycin is so called because it was isolated from Streptomyces bottropensis.
Examples of compounds similar to borrelidin include the naturally occurring mupirocin, used to treat bacterial skin infections and febrifugine, the active component of a Chinese herb called Chang Shan, which has been used to treat the fever caused by malaria for thousands of years.
Why were you interested in studying borrelidin?
Our major research interest is in the inhibition of a certain type of enzyme called threonyl-tRNA synthetase (thrRS), which contributes to the quality control of protein synthesis.
tRNA (transfer RNA) is essential to protein synthesis and interfering with its production can disrupt protein synthesis and ultimately shut an organism down. Although other compounds in this class have already been used as antimicrobials, studies have shown that borrelidin is the most potent inhibitor in the group.
Borrelidin also provides an important starting point for the discovery of anti-malarial mechanisms, as it displays activity against drug-resistant Plasmodia.
Furthermore, borrelidin has been shown to interfere with the formation of new blood vessels (a process called angiogenesis) and to induce apoptosis of cells that form the capillary tube. This could significantly benefit cancer research, because a tumor uses angiogenesis to create its own blood supply in order to receive nutrients and grow.
What have previous studies revealed about borrelidin?
They have shown that it’s really a multifunctional inhibitor. The compound is very powerful, with wide-ranging anti-bacterial, anti-fungal, anti-malaria and anti-cancer effects.
How much is known about how borrelidin works?
Little is known about how borrelidin functions, but these type of inhibitors show great potential in a number of clinical applications.
Please can you outline your recent study and your main findings?
We conducted our research to try and shed light on the mechanism underlying how borrelidin binds to human and bacterial ThrRS. We performed a detailed analyses of the structure and function of borrelidin in terms of how it binds to ThrRS and the results were very surprising.
We found that on both human and bacterial ThrRS, borrelidin takes up four subsites, each of which are crucial to its activity.
Three of the subsites already exist for the normal binding of substrates and another one is produced when borrelidin binds to the enzyme. This prevents all natural substrates that would otherwise bind those sites and induce protein synthesis from doing so.
This type of “inhibitory overkill” helps explain the potency of borrelidin that has been demonstrated in previous studies.
Were you surprised by this mechanism?
Yes, this binding mechanism has not been seen before in any other inhibitors of tRNA synthetases, including the products currently on the market.
The striking design of this compound that can inhibit tRNA synthetases in both humans and bacteria, puts borrelidin in an inhibitor class of its own
What impact will this understanding of borrelidin’s mechanism have?
This will have an impact in general medicine, because it is always challenging to develop the next generation of antibiotics. This actually provides us with a platform for generating a much more potent antimicrobial.
How important do you think our understanding of borrelidin will be in the future of treatments for microbial infections and cancer?
It’s a really excellent platform for the design of anti-bacterial, anti-angiogenesis and anti-cancer agents and will hopefully lead to the development of improved compounds in the future.
Where can readers find more information?
The Guo Lab
Nature Communications
About Dr Min Guo
Min Guo received his Ph.D. in structural biology from the University of Science and Technology of China in 2005 and then became a postdoctoral fellow at The Scripps Research Institute, La Jolla, California, USA, where he studied structures and multiple functions of aminoacyl-tRNA synthetases (aaRSs).
Dr. Guo is a Sydney Kimmel Scholar for Cancer Research and an American Asthma Foundation Scholar. He is currently an Associate Professor in the Department of Cancer Biology at The Scripps Research Institute, Florida, USA, where he is investigating the role of aaRSs in cancer etiology.
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