A Breakthrough in Antibiotic Development

Did you know that not all types of bacteria in this world are harmful to humans? Some bacteria can be used in the production of cheese, and can even be used to manufacture antibiotics for human use. Dr. Jason Hedges and Dr. Katherine Ryan of the University of British Columbia took a look into finding new ways to produce antibiotics from bacteria. 

Their recent publication in 2019 showed how they were able to convert an amino acid (a building block of proteins) into a modern day antibiotic.

Antibiotics are used to cure bacterial infections by killing bacteria. For example,  an antibiotic called penicillin was used extensively in the 19th century to save thousands of lives.

As Amazing as they Sound, Antibiotics are not a Permanent Solution

The over-usage of antibiotics results in bacteria that can build resistance to them and cause the medication to be ineffective. 

The World Health Organization announced: “A serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone” on development of drug resistant bacteria.

Once a type of bacteria develops a resistance to a specific antibiotic, other antibiotics must be used in its place to treat the infection. 

Nitroimidazoles are a group of antibiotics which have been used for decades. Due to its low resistance by bacteria, it has been used extensively to treat bacteria that have developed a resistance to certain antibiotics.

This is the chemical structure of azomycin. Azomycin is a type of antibiotic that falls under the family of antibiotics labelled nitroimidazoles. It is used to treat drug resistant bacteria.

Diving into the Research

The researchers used bioinformatics, a data analysis tool, to find all previous work that has been done on this topic. Bioinformatic searches are performed on databases such as the NCBI.

They found that back in 1953, azomycin (a type of nitroimidazole) was produced by a strain of bacteria that is found in the soil. The researchers adapted this old method by applying modern techniques to it, in an attempt to produce azomycin in a different strain of soil bacteria called Streptomyces cattleya.

The two researchers aimed to find new ways to synthesize azomycin, and proposed that it could be done by using an amino acid called arginine. Once a pathway connecting arginine to azomycin had been developed, their end goal was to synthesize and extract azomycin in Streptomyces cattleya.

Hedges and Ryan were able to develop a multi-step pathway for the conversion of arginine to azomycin through experimentation. However, they were unable to detect any azomycin in the bacteria itself.

They noted that the bacteria of interest was unable to synthesize azomycin, and a separate drug or antibiotic may have produced in its place.

A simplified overview of converting an amino acid (Arginine) into an antibiotic drug (Azomycin).

A Bright Future

The significance of this research transcends the synthesis of azomycin. Although they failed to detect azomycin in Streptomyces cattleya, their work provides a stepping stone for further research to be conducted. 

This study provides insight on new biosynthetic pathways which is important to those currently in the field of life sciences and pharmacology. 

Furthermore, this study expands people’s knowledge of bacteria engineering and how antibiotics are created.

In the near future, researchers could test their synthetic pathway on other bacteria such as E. coli to determine if azomycin could be produced. This will allow for the production of more antibiotics, or even the discovery of new antibiotics.

 

Reference:

Hedges, J. B.; Ryan, K. S. In Vitro Reconstitution of the Biosynthetic Pathway to the Nitroimidazole Antibiotic Azomycin. Angewandte Chemie International Edition 201958 (34), 11647–11651.

 

– Adrian Emata, Vicky Gu, Jackson Kuan, Yicheng Zhu

LIFE-SAVING IMPROVEMENTS To Blood Transfusions

Have you ever ended up in the hospital and needed a blood transfusion? Well, that’s about to get a whole lot easier for people everywhere! An article published by Nature Microbiology in June 2019 by Dr. Stephen Withers, studied a new method in converting type A blood to the universal type O blood using bacteria found in the human gut! [1] 

A team led by Dr. Stephen Withers at the University of British Columbia has developed a method which would eliminate the need for blood-type compatibility, reducing the risks of blood transfusions.  

What are blood types? 

There are 8 different blood types, and before these findings, these blood types were not all compatible with each other. Each blood type can only receive from other specific types.  

In human bodies, there are 8 types of red blood cells. These types are determined by two factors: Blood Groups and Rh Factors. 

We have 4 different blood groups: A, B, AB and O, different blood groups carry different signals (see Image 1).O-type cells do not carry any signals.

 Similarly, Rh-positive red blood cells carry another signal, and Rh-negative cells carry nothing. Blood groups and Rh factors are combined, so that we have blood types such as A positive, O negative, etc.

Image depicting the different signals on red blood cells. Created by Eric Ding using PowerPoint.

If we transfuse  O negative cells, which do not carry any signals, they can be recognized by anyone with any type of blood. 

 However, if we transfuse A positive red blood cells to a patient with AB negative blood, the immune system can recognize the triangle signal, but not the rectangular signal. The body will consider A positive red blood cells as enemies and attack them. This reaction can be fatal.

This problem has existed since blood transfusions were first scientifically achieved, and scientists have been looking for a solution for just as long. It turns out the solution was hiding right under our noses; inside our stomachs, to be specific!

The findings

Inside the human gut are thousands of microscopic bacteria which we use to digest food and convert it into energy. As it turns out, these bacteria are very good at safely interacting with the human body in helpful ways.

The researchers removed these bacteria through human faeces and found they could be used in exactly the way they were hoping. “Why would they be looking in our stomachs for this solution?” you might ask.

 The Withers group were on a hunt for a special kind of protein called an enzyme. Enzymes are produced by the body with a very specific task, and that task varies based on what the body wants it to do.

 Since our gut has the ability to process blood and turn it into energy, Withers and his team decided to see if these enzymes could be harnessed for their research.  As it turns out, they were completely correct.

An enzyme interacting with a specific molecule (known as the substrate) and cutting it into two different products. Modified from Wikipedia Commons.

The group screened more than 20,000 samples to find two enzymes that were particularly good at cutting the signal on A-type blood leaving us with O-type blood. These were removed from the body and tested on real red blood cells.  

The researchers discovered that the enzymes could efficiently cut the specific part of the A-type blood, essentially leaving us with type O red blood cells.

 These two types of enzymes were 30 times more efficient than previous methods, which means we only need a tiny amount of these enzymes to convert A, B, and AB types of red blood cells to O type red blood cells.

Impacts

In January 2020, the American Red Cross announced that it has a ‘critical’ shortage of type O blood. In the United States and Canada alone, 4.5 million patients need blood transfusions every year.[2] 

This high demand means that oftentimes, the supply cannot meet the demand.

 With this new discovery, incompatible blood types can be made compatible. This would increase the supply of compatible blood, which means more people can be helped.

While the process has been completed in the lab, it has yet to be scaled up to convert massive amounts of blood at a time.  This may take some time to accomplish. 

However, countless people will be helped and countless lives will be saved. And if one thing is for certain, it’s that blood donations will forever be easier.

References
  1. Rahfeld, P., Sim, L., Moon, H., Constantinescu, I., Morgan-Lang, C., Steven, J. H., Kizhakkedathu, J. N., Withers, S. G.; An enzymatic pathway in the human gut microbiome that converts A to universal O type blood. Nature Microbiology. 2019, 1475-1485.
  2. Community Blood Bank of Northwest Pennsylvania and Western New York. 56 facts about blood. https://fourhearts.org/facts/ (accessed March 22, 2020)

– Griffin Bare, Eric Ding, Chantell Jansz

Exploring Caffeine to Expand the Pharmaceutical World

What do the effects of the chemicals in caffeine tell us? Researchers at the University of British Columbia, led by Dr. Laurel Schafer, answers this question, in 2019, by developing an efficient method to produce a similar chemical, known to be used in various applications. 

A starting material reacts with a chemical in a determined set of conditions to yield a single product. This product identifies itself as a class of pseudoalkaloids.

Pseudoalkaloids can be described by their use for biological activity and exhibit enhanced properties compared to alkaloids, such as cancer treatment. Pharmaceutical industries often investigate biological activities of alkaloids to use them for drugs. 

If you are a coffee lover, you probably know the naturally occurring substance, caffeine, and its stimulating properties to our nervous system. Caffeine is classified as a pseudoalkaloid.

Using a special type of reaction, these alkaloids can be created with materials that are compatible with each other. Past studies can be improved to target specific types of pseudoalkaloids by changing the materials and methods used.

Pseudoalkaloids can be artificially made, but time-consuming multiple synthetic steps limit the production of  pseudoalkaloids. Importantly, the challenge lies in the reactivity of the starting materials, and whether it can react to produce the desired pseudoalkaloid without byproducts. 

This proves to be a challenge because structurally complex or large chemicals have a hard time to mingle with their pairs. As such, this gives rise to multiple unwanted products, as seen in similar studies.

The solution lies within the tantalum catalyst, a tool that speeds up and controls the reaction, which is tested on a reaction to observe its effectiveness on producing the final product. Existing studies experimented with different types of metal catalysts and show a high potential for great results.

An idea was proposed to add molecules that bind to the tantalum catalyst. This binding molecule improves the reactivity of the catalyst and proceeds the reaction, thereby converting as much initial material as possible to the final product.

After many attempts of finding the perfect combination of chemicals to react in the optimal conditions, Dr. Laurel Schafer’s group has synthesized the desired pseudoalkaloid of interest. For public use, the product is isolated and purified easily, since the reactivity of the reaction is maximized.

The experiment is deemed successful as it tackled all the problems faced from past researchers. One example is the selectivity of the reaction, where the reaction conditions can structurally change the final product and display undesired applications.

Evidence proves the benefits of developing pseudoalkaloids, like caffeine, and hold significant demand in the public. It is possible to design synthetic methods to produce different pseudoalkaloids with caffeine in mind. 

 

 Reference

Dipucchio RC, Rosca SC, Athavan G, Schafer LL. Exploiting Natural Complexity: Synthetic Terpenoid‐Alkaloids by Regioselective and Diastereoselective Hydroaminoalkylation Catalysis. ChemCatChem. 2019;11(16):3871–6.

-Group 9 (Wilson, Young, Rachel)

 

Sugars – The Key to Talking to Our Cells

We are one step closer to achieving communication with those 37.2 trillion tiny cells making up our bodies. Just last year, researchers at the University of British Columbia, led by Dr. Stephen Withers, found a way to modify the sugars essential to this communication by using chemicals found in bacteria. The same bacteria living in our gut!

WHAT EXACTLY ARE SUGARS?

No ambiguity here! Chemists work with sugars based off molecules in this sugar cube. Credits: The Verge

To be specific, the sugars Withers’ team studied were simple sugars; hexagonal-shaped molecules, often joined to other molecules known as “acceptors”. The problem chemists face is like the average love life. 

Similar to starting a relationship with someone, joining acceptors to sugars is also quite difficult. Luckily for sugars, Mother Nature has come up with some solutions: enzymes, which are helper molecules that speed up the pairing or unlinking of two molecules.

A SOLUTION UNDER OUR NOSES…

Instead of struggling to find ways of joining sugars and acceptors, Withers’ team thought: Why not hijack Mother Nature and use these enzymes? To make their idea a reality, they extracted sugar-specific enzymes from E. Coli, a type of bacteria that lives inside the human gut.

These bacteria manufactured 175 sugar-specific enzymes, and from these they chose eight enzymes that were compatible with the sugars and acceptors they were interested in.

It seemed like Withers’ team now had everything needed to join the desired acceptors to the sugars; however, there was still a problem. The sugar-specific enzymes they got from E. Coli did the exact opposite of what they wanted; instead of forming sugar-acceptor linkages, they specialized in breaking them.

Enzymes that break sugar-acceptor linkages are analogous to using a screwdriver to loosen a screw, while enzymes that form sugar-acceptor linkages are like tightening a screw.

A small modification changes the function of the enzyme. Credits: Blog post authors

To solve this problem, they reverse-engineered the enzymes specialized in breaking linkages into those that form linkages, by changing a small part of the enzymes’ structure, similar to changing the tips on a screwdriver. As a result, Withers’ team now had eight enzymes specialized in forming different sugar-acceptor linkages. 

MORE THAN JUST A BOND…

Now being able to freely and efficiently modify sugars, there is a big potential for researchers to join in on the conversations with our cells. Why is this important? Often, there is miscommunication within our cells which can lead to serious trouble. 

One example is cancer; which is partly caused by cancer cells using abnormal sugar molecules as a form of miscommunication, to avoid being cleared up by immune cells. One potential treatment is a sugar-based vaccine, which allows our immune cells to more efficiently target tumor cells.

The challenge of creating a sugar-based vaccine isn’t just relevant to cancer, but other diseases as well which also occur  as a result of miscommunication. With Withers’ research, designing these sugar-based drugs won’t be as difficult thanks to their novel way of bonding sugars to other molecules. This research brings us one step closer to talking to our cells, helping with the battle against diseases.

Story source

Armstrong, Z.; Liu, F.; Chen, H.-M.; Hallam, S. J.; Withers, S. G. Systematic Screening of Synthetic Gene-Encoded Enzymes for Synthesis of Modified Glycosides. ACS Catalysis 20199 (4), 3219–3227.

– Kenny Lin, Pricia Ouyang, Tom Hou, Aron Engelhard (CO-10)

H2hox and Gallium: A Dynamic Duo in Medical Imaging

Not every molecule gets to find their best “partner” in life. Luckily in 2019, Dr. Chris Orvig and his team at the University of British Columbia constructed a partner molecule for Gallium to work with in medical imaging. They also determined that their creation has superior stability and binding ability compared to similar molecules currently being used.

THE NEW MOLECULE IN TOWN

The partner molecule is a chelating ligand known as H2hox. Let’s break down its name piece-by-piece to get a better understanding of what it does.

A ligand is a molecule that binds onto a metal ion such as iron (Fe3+) or copper (Cu2+). In the case of H2hox, the metal ion is Gallium (Ga3+ ).

The word chelating comes from the latin root word chela, which means claw. This is because chelating ligands have multiple points of attachment to a metal ion, similar to a crab’s claw, making them significantly stronger binders to metal ions.

Image sources (left to right): Research Gate, Wang et al..

THE DUO GETS TO WORK

H2hox is used in a form of medical imaging known as positron-emission tomography (PET). PET imaging is used to diagnose health issues related to the processes occurring inside our cells, such as cancer.

The main function of H2hox in PET imaging is to bind to radioactive Gallium ions, which aids in producing an image of a desired area or tissue inside the body.

To test how well H2hox worked together with its partner, Gallium, the researchers conducted a PET scan in mice. The group witnessed high stability of the dynamic duo within mice, and they observed that it was rapidly excreted from the mice, which is important for a decrease in side effects.

Furthermore, the ligand has a strong affinity to Gallium, such that only low amounts of ligand are needed to significantly bind to Gallium ions in just five minutes! As a result of the molecule’s advanced properties, H2hox surpasses any ligand currently used as a Gallium’s partner.

ALL IT TAKES IS 1 STEP

In the lab, H2hox is synthesized (made) in only one reaction and is easy to purify, unlike similar ligands which are synthesized over multiple labor- and resource- intensive steps. As a bonus, the chemicals used to make it are inexpensive and readily available.

To put this into perspective, it’s like baking a box cake versus baking a cake from scratch. The former is quite easy to do, while the latter is a lot harder and is more labour-intensive. Ease of manufacturing is a key feature because it determines the commercial success of the product.

THE FUTURE IS PROMISING

The combination of unprecedented properties and easy synthesis makes H2hox a launching-off point for the development of even better chelating ligands to improve the future of PET imaging. With H2hox being such an advantageous molecule for Gallium PET imaging, we cannot wait to see what else this dynamic duo has to offer the world.

Literature cited:

  1. Wang, X.; Jaraquemada-Pelaez, M. d. G.; Cao, Y.; Pan, J.; Lin, K.-S.; Patrick, B.O., Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals. J. Am. Chem. Soc. 2019, 58, 2275-2285

 

-Group 6 (Mark, Akash, Athena, Charles)

Life-saving improvements to blood transfusion

An article published by Nature Microbiology in June 2019, studied a new method in converting type A blood to the universal type O blood using bacteria found in the human gut! [1] A team led by Dr. Stephen Withers at the University of British Columbia has developed a method which would eliminate the need for blood-type compatibility, reducing the risks of blood transfusions.  

There are 8 different blood types, and before these findings, these blood types were not all compatible with each other. Each blood type can only receive from other specific types.  When doctors are going to transfuse blood to patients, they need to match the type of blood to one that can safely match with the patient’s blood type. If they don’t, the body will not know how to handle the new type of blood. This can cause blood vessels to rupture, which can be fatal.

This problem has existed since blood transfusions were first scientifically achieved, and scientists have been looking for a solution for just as long. It turns out the solution was hiding right under our noses; inside our stomachs, to be specific!

Inside the human gut are thousands of microscopic bacteria which we use to digest food and convert it into energy. As it turns out, these bacteria are very good at safely interacting with the human body in helpful ways. The researchers extracted these microorganisms through human faeces and found they could be used in exactly the way they were hoping.

         “Why would they be looking in our stomachs for this solution?” you might ask. The Withers group were on a hunt for a special kind of protein called an enzyme. Enzymes are produced by the body with a very specific task, and that task varies based on what the body wants it to do. Since our gut has the ability to process blood and turn it into energy, Withers and his team decided to see if these enzymes could be harnessed for their research.  As it turns out, they were completely correct.

An enzyme interacting with a specific molecule (known as the substrate) in the body.[2]

The group screened more than 20,000 samples to find two enzymes that were particularly good at cleaving the A-type blood. These were extracted and tested on real red blood cells and found that the enzymes could efficiently cleave a specific part of the A-type blood, essentially leaving us with type O red blood cells. These two types of enzymes were 30 times more efficient than previous methods, which means we only need a tiny amount of these enzymes to convert A, B, and AB types of red blood cells to O type red blood cells.

Image depicting the difference between blood types A, O, and B. The image shows that removing the yellow square in A type blood, is the same as O type blood. Modified from [1].

In January 2020, the American Red Cross announced that it has a ‘critical’ shortage of type O blood. In the United States and Canada alone, 4.5 million patients need blood transfusions every year.[3] This high demand means that oftentimes, the supply cannot meet the demand. With this new discovery, incompatible blood types can be made compatible. This would increase the supply of compatible blood, which means more people can be helped.

While the process has been completed in the lab, it has yet to be scaled up to convert massive amounts of blood at a time.  This may take some time to accomplish. However, it is impossible to quantify exactly how many people this new method will help, or even how many lives it will save. One thing is for certain, the world of blood donations will forever feel the impact of these findings.

References
  1. Rahfeld, P., Sim, L., Moon, H., Constantinescu, I., Morgan-Lang, C., Steven, J. H., Kizhakkedathu, J. N., Withers, S. G.; An enzymatic pathway in the human gut microbiome that converts A to universal O type blood. Nature Microbiology. 2019, 1475-1485.
  2. Western Oregon University: Chemistry. CH450 and CH451: Biochemistry – Defining Life at the Molecular Level. Chapter 6: Enzyme Principles and Biotechnological Applications. https://wou.edu/chemistry/courses/online-chemistry-textbooks/ch450-and-ch451-biochemistry-defining-life-at-the-molecular-level/chapter-7-enzyme-kinetics/ (accessed Mar 21, 2020)
  3. Community Blood Bank of Northwest Pennsylvania and Western New York. 56 facts about blood. https://fourhearts.org/facts/ (accessed March 22, 2020)

– Griffin Bare, Eric Ding, Chantell Jansz

Sugars – The Key to Talking to our Cells

We are one step closer to achieving communication with those 37.2 trillion tiny cells making up our bodies. Our cells communicate using sugars, and different modifications to these sugars can change the way our cells communicate with each other. Just last year, researchers at the University of British Columbia, led by Dr. Stephen Withers, did exactly this! They designed a unique way to tinker with sugars’ chemical structures by using chemicals found in bacteria. The same bacteria living in our gut.

what exactly are sugars?

No ambiguity here! Chemists work with sugars based off molecules in this sugar cube. Credits: The Verge

To be specific, the type of sugars Wither’s team studied were simple sugars; hexagonal-shaped molecules, often joined to other molecules known as “acceptors”. The problem chemists face is like the average love life. Similar to starting a relationship with someone, joining acceptors to sugars is also quite difficult. Luckily for sugars, Mother Nature has come up with some solutions: enzymes, which are helper molecules that speed up the pairing or unlinking of two molecules. 

A SOLUTION UNDER OUR NOSES…

Instead of struggling to find ways of joining sugars and acceptors, Wither’s team thought: Why not hijack Mother Nature and use these enzymes? To make their idea a reality, they extracted sugar-specific enzymes from E. Coli, a type of bacteria that lives inside the human gut. These bacteria manufactured 175 sugar-specific enzymes, and from these they chose eight enzymes that were compatible with the sugars and acceptors they were interested in.

It seemed like Wither’s team now had everything needed to join the desired acceptors to the sugars; however, there was still a problem. The sugar-specific enzymes they got from E. Coli did the exact opposite of what they wanted; instead of forming sugar-acceptor linkages, they were specialized in breaking them. Enzymes that break sugar-acceptor linkages are analogous to using a screwdriver to loosen a screw, while enzymes that form sugar-acceptor linkages are like tightening a screw.

A small modification changes the function of the enzyme. Credits: Blog post authors

To solve this problem, they reverse-engineered the enzymes specialized in breaking linkages into those that form linkages, by changing a small part of the enzymes’ structure, similar to changing the tips on a screwdriver. As a result, Wither’s team now had eight enzymes specialized in forming different sugar-acceptor linkages. 

More than just a bond…

Now being able to freely and efficiently modify sugars, there is a big potential for researchers to join in on the conversations with our cells. Why is this important? Often, there is miscommunication within our cells which can lead to serious trouble. 

One example is cancer; which is partly caused by cancer cells using abnormal sugar molecules as a form of miscommunication, to avoid being cleared up by immune cells. One potential treatment is a sugar-based vaccine, which tells our immune cells to ignore this miscommunication and target tumor cells.

The challenge of designing a sugar-based vaccine isn’t just relevant to cancer, but other diseases as well which occur also as a result of miscommunication. With Wither’s research, designing these sugar-based drugs won’t be as difficult thanks to their novel way of bonding sugars to other molecules. This research brings us one step closer to talking to our cells, helping with the battle against diseases.

Story source

Armstrong, Z.; Liu, F.; Chen, H.-M.; Hallam, S. J.; Withers, S. G. Systematic Screening of Synthetic Gene-Encoded Enzymes for Synthesis of Modified Glycosides. ACS Catalysis 20199 (4), 3219–3227.

– Kenny Lin, Pricia Ouyang, Tom Hou, Aron Engelhard (CO-10)

Magical Materials Revolutionize the Pharmaceutical World

What if there’s more to caffeine than meets the eye? What if we can chemically change the way caffeine works to create a better version of itself. 

If you are a coffee lover, you probably know the naturally occurring substance, caffeine, and its stimulating properties to our nervous system. Why and how does it happen?

Using a special type of reaction, the biological activity of caffeine can be transformed to suit a variety of different applications. Past studies can be improved by changing the materials needed and the methods used. 

Dr. Schafer’s team, at the University of British Columbia, examines an approach to synthesize pseudoalkaloids (Fig. 1), chemicals present in caffeine, with great accuracy.

Figure 1. Examples of pseudoalkaloids. The pseudoalkaloids on the left are produced naturally or synthetically. The pseudoalkaloids on the right are the researchers’ target molecules. (molecules were drawn with ChemDraw 19.0; Credits: Wilson, Young, and Rachel)

Pseudoalkaloids can be artificially made, but time-consuming multiple synthetic steps limit the production of  pseudoalkaloids. Importantly, the challenge lies in the reactivity of the starting materials, and whether it can react to produce the desired pseudoalkaloid without byproducts. 

Similar studies show different products have formed, which proves to be a problem. 

Existing studies experimented with different types of metal catalysts showing potential improvement for the results. A tantalum catalyst, a tool that speeds up the reaction, is tested on a reaction to observe its effectiveness on producing the final product. 

An idea was proposed to add molecules that bind to the tantalum catalyst. This binding molecule improves the reactivity of the catalyst, thereby converting as many initial materials as possible to the final product.

Of many possible starting materials, terpenes (Fig. 2) were used for the synthesis of pseudoalkaloids. In addition to the inactive alkene groups in terpenes, various chemical structures make them attractive starting substrates to explore a new synthetic route. 

Figure 2. Examples of terpenes. Terpenes are naturally occurring organic molecules, produced by plants. The terpenes on the right are starting materials chosen by the researchers. Every terpene has unsaturated functional groups which may react with other molecules.  (molecules were drawn with ChemDraw 19.0; Credits: Wilson, Young, and Rachel)

Another key building block, an amine, can be any, as long as the nitrogen atom of an amine is directly bound to one hydrogen atom. However, a clever choice can even make the final products useful building blocks, allowing further modifications (Fig. 3)

 Figure 3. Amines with varying R groups. After reacting with a terpene, the R group of pseudoalkaloid can be further modified to form a new molecule. (molecules were drawn with ChemDraw 19.0; Credits: Wilson, Young, and Rachel)

The catalytic reaction between amines and terpenes with the tantalum catalyst showed great selectivity. Without the help of the tantalum catalyst, an amine could potentially select any active spot on a terpene and react with it, causing a mixture of pseudoalkaloids at the end of the reaction.

However, the tantalum catalyst results in one dominating product. Although the final pot contains some residual starting materials, the target pseudoalkaloids are the major product that can be easily isolated.

By constructing a pathway to ultimately arrive at the designated point, new and better options can be achieved. Caffeine is one of many that can be innovated upon.

 

Reference

Dipucchio RC, Rosca SC, Athavan G, Schafer LL. Exploiting Natural Complexity: Synthetic Terpenoid‐Alkaloids by Regioselective and Diastereoselective Hydroaminoalkylation Catalysis. ChemCatChem. 2019;11(16):3871–6.

 

-Group 9 (Wilson, Young, Rachel)

 

The Next Step in Antibiotics

Did you know that not all types of bacteria in this world are harmful to humans? Some bacteria can be beneficial such as those used for the production of cheese and yogurt. Furthermore, these tiny creatures could even potentially be used to manufacture antibiotics for human use.

Antibiotics are used to cure bacterial infections by killing bacteria. For example, penicillin saved thousands of people in the 19th century.

Bacteria

As Amazing as they Sound, Antibiotics are not a Permanent Solution

The over-usage of antibiotics results in bacteria that can build resistance and cause the medication to be ineffective. The World Health Organization announced: “A serious threat is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone” on the development of drug-resistant bacteria.

Once a type of bacteria develops a resistance to a specific antibiotic, other antibiotics must be used to treat the infection. For example, nitroimidazole is a drug found in antibiotics such as azomycin. Due to its low resistance by bacteria, it has been used extensively to treat bacteria that have developed resistance to certain antibiotics.

Nitroimidazole

Research Looking into Nitroimidazole

Dr. Jason Hedges and Dr. Katherine Ryan of the University of British Columbia took a look into finding new ways to synthesize nitroimidazole. Their recent publication in 2019 showed how they were able to convert an amino acid (a building block of proteins) into azomycin. 

The researchers used bioinformatics, a data analysis tool, to find all previous work that has been done on this topic. Bioinformatic searches are performed on databases such as NCBI.

They found that back in 1953, azomycin was extracted from a strain of bacteria called Streptomyces eurocidicus. Furthermore, they found a specific gene in a separate strain of yeast called Streptomyces cattleya, which had similarities to S. eurocidicus

The two researchers aimed to find new ways to synthesize nitroimidazole, and proposed to synthesize nitroimidazole from L-arginine. Once a pathway had been developed, their end goal was to synthesize and extract azomycin in S. cattleya.

Hedges and Ryan were able to develop a multi-step pathway for the conversion of L-arginine to nitroimidazole through experimentation. However, they were unable to detect azomycin in S. cattleya. They noted that the gene of interest was unable to synthesize azomycin, and a separate drug may have synthesized in its place.

Synthesize of nitroimidazole from L-Arginine

A Bright Future

The significance of this research transcends the synthesis of azomycin. Although they failed to detect azomycin in S. cattleya, their work provides a stepping stone for further research to be conducted. This study provides insight on new biosynthetic pathways which is important to those currently in the field of life sciences and pharmacology. Furthermore, this study expands people’s knowledge of bacteria engineering and the biosynthetic pathway of other antibiotics. It also provides information about future antibiotic observations.

Future researchers could test their synthetic pathway on other bacteria such as E. coli to determine if azomycin could be synthesized.

Reference:

Hedges, J. B.; Ryan, K. S. In Vitro Reconstitution of the Biosynthetic Pathway to the Nitroimidazole Antibiotic Azomycin. Angewandte Chemie International Edition 2019, 58 (34), 11647–11651.

-Adrian Emata/Jackson Kuan/Xinyu Gu/Yicheng Zhu

 

 

 

A New and Advantageous Molecule for Diagnostic Nuclear Medicine

You may be aware of the role physicists and doctors play in diagnostic nuclear medicine; however you may not know that chemists also play a significant role in this area of science! In 2019, Dr. Chris Orvig and his team at the University of British Columbia constructed an advantageous molecule for use in medical imaging whose purpose is to bind to radioactive Gallium (Ga) ions. They also determined that their molecule has superior properties to similar molecules currently being used.

WHAT IS IT?

The molecule that was created by Dr. Orvig’s team is simply known as H2Hox , a chelating ligand. Let’s break its name down piece-by-piece to get a better understanding of what it does.

A ligand is a type of molecule that can bind onto a metal ion, like iron (Fe3+) or copper (Cu2+). In the case of H2hox, the metal ion is Gallium (Ga3+) because it is widely used in medical imaging. The word chelating comes from the latin root word chela, which means claw. This is because chelating ligands have multiple points of attachment to a metal ion, similar to a crab’s claw, making them significantly stronger binders to metal ions.

Image sources (left to right): Research Gate, Wang et al..

HOW IS IT MADE?

H2Hox is easy to synthesize, avoiding a number of potentially challenging synthetic pathways typically associated with Ga chelating species. The initial starting materials were inexpensive and readily available. To put this into perspective, it’s like baking a box cake versus baking a cake from scratch. The former is simple and quite easy to do, while the latter is a lot harder and is a lot more intensive. Ease of synthesis is an important feature as it can affect the commercial applicability of the molecule.

WHAT DOES IT DO?

H2Hox is used in a form of medical imaging known as positron-emission tomography (PET). PET imaging is primarily used to diagnose health issues related to biochemical processes occurring inside our cells, such as cancer. The main function of H2Hox in PET imaging is to bind to the radioactive Gallium ion, which aids in producing an image of a desired area or tissue inside the body.

To test how well H2Hox worked, the researchers conducted a PET scan in mice. The group witnessed high stability of the combined ligand and ion in mice, and more importantly, they observed that it was rapidly excreted from the mice. Furthermore, the ligand has a strong affinity to Gallium, exhibiting significant radiolabeling capabilities (binding to Ga3+) in only five minutes with low amounts of ligand under room temperature. As a result of the molecule’s advanced properties, H2Hox surpasses any ligand currently used as a Gallium chelator.

THE FUTURE IS PROMISING

The combination of superior properties and easy synthesis makes H2Hox an effective and convenient molecule for Gallium PET imaging. H2Hox acts as a launching-off point for the development of even better chelating ligands to improve the quality and ease of PET imaging.

Literature cited:

1. Wang, X.; Jaraquemada-Pelaez, M. d. G.; Cao, Y.; Pan, J.; Lin, K.-S.; Patrick, B.O., Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals. J. Am. Chem. Soc. 201958, 2275-2285

 

-Group 6 (Mark, Akash, Athena, Charles)