Category Archives: Uncategorized

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

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)

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)

Biosynthetic Pathway Found to Synthesize Anaerobic Antibiotics!

Fig 1. Image of Azomycin. source

Scientists found the biosynthetic pathway to the Nitroimidazole Antibiotic Azomycin. A steppingstone towards the revolution of anaerobic bacterial infection treatments.

Scientists from the University of British Columbia found the biosynthetic pathway to the Nitroimidazole antibiotic Azomycin. The enzymatic mechanism from L-Arginine to Nitroimidazole has now been proved and present to the public. Their formal paper was published online on July 17th, 2019. Nitroimidazole is an essential component for the modern antibiotics, it is crucial to know its synthetic pathway for further pharmaceutical studies. The result of their study set the stage for further development of important anaerobic antibiotic Azomycin.

What is it? Why do we need to know about this?

Nitroimidazole is an essential antibiotic specifically to treat anaerobic bacterial infections. They are widely used to treat diseases such as Amoebiasis, Parasitic infections, skin infections, diarrhea and so on. The low redox potential of anaerobic bacteria cells allowed nitroimidazole to act as the electron sink and form the radical species. The resultant radical species would induce the bacteria cells’ death by damaging their DNA. Antibiotic is the most powerful “weapon” to fight against bacterial infections. However, according to the World Health Organization, there are more than 700000 people die every year due to antibiotic resistance. Despite the several decade’s usages of Nitroimidazole antibiotics, the drug resistance of it still remains low relatively. Thus, Nitroimidazole antibiotics are increasingly used to treat multi-drug resistant bacteria as well.

 

Previous research established that L-Arginine is converted to azomycin by 2-aminioimidazole. They determined that the intermediate of the reaction is 4-hydroxy-2-ketoarginine (2). Furthermore, they also observed the accumulation of pyruvate(3) side products and 2-aminoimidazole(5) from the intermediate(2). However, the actual enzymatic synthetic pathway has not been determined detailly yet. Jason and Katherine in the research group determined that PLP-dependent enzymes, RohP,RohR,RohQ and RohS plays esstential role in the catalytic pathway of the reaction. Researchers examined the in vitro activity of RohP, RohR, RohQ and RohS. They put in these enzymes separately and stepwise to different reactants. For example, in order to test whether RohR could catalyze a retro-aldol cleavage of 2 into 3 and guanidinoacetaldehyde (4), they added purified RohR instead of RohP. Then according to activity analysis and also the mass spectrum, the result shows that RohP yields a bigger portion of 2.

Fig 2. Reaction scheme from L-Arginine to Nitroimidazole. Source

Antibiotics are the most powerful “weapon” to kill bacteria in modern pharmaceutical studies. As early as in the 20th century, the observation of penicillin saved millions of people injured in the World War. Yet, the enormous benefits of antibiotics cause the consequences of drug-resistance. Azomycin, consider as a low-resistance antibiotic, it is crucial to understand its enzymatic reaction mechanism. Reaction mechanism allows scientist to have a more detail interpretation of the synthesis. It is crucial to find the catalytic cycle of the reaction, in order to allow scientists to develop and derive further study.

The study done by Jason and Katherine at the University of British Columbia provides the public with a steppingstone in future nitroimidazole anti-biotics study. Their study expanded people’s knowledge of the biosynthetic pathway to nitro-compounds. It also makes bacteria engineering to produce nitroaromatic compounds possible. This study will open the new door in enzymatic synthesis and biochemistry synthesis.

Cited article:

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.

The Revolutionary Progress in Radiopharmaceutical that Shocked the Whole World

Cancer is a disease that killed 8.9 million people by 2016, and it is very hard to detect. For someone suffering cancer, they may want to detect it as early as possible so they can be treated. In the past, doctors have to take a patient’s tissue. With naked eyes, the doctor has to search for tiny cancer monsters in this tissue under a microscope, which is like searching a needle in an ocean. Even for highly-experienced doctors, this process is time-consuming and has a high chance of miss-detecting.

Cancer Deaths
(Source: Our World Data)

Now there are radioactive chemicals that can efficiently detect cancer cells. It works like this. There is a blue-colored chew-chew train in these chemicals called a positron, which collides with the red chew-chew train in your body called an electron. When they collide, they annihilate each other and make huge lightning like in a nuclear bomb. These lights are so strong that they can penetrate through your body and be captured by our detecting machine. So you might wonder, how do we know if there are cancer monsters then? Well, the cancer monsters can eat away light, so when the detecting machine receive light from areas of the patient’s body where cancer cell is present, the picture coming out would be much, much darker.

chew-chew trains colliding (source: google)

But here is another problem–––the radioactive chemicals are so dangerous that they can destroy your body, which is also why we make nuclear bombs out of them. Therefore scientists have found types of these chemicals that only explode for a few hours, on top of them is something called Germanium, it is not made in Germany, but you could memorize it that way. It’s not just normal Germanium, but a thin, thin Germanium that is a little lighter than the normal Germanium.
But the problem has not been solved. What if the Germanium jumps around your body and destroys everything? We need a claw that clamps onto this Germanium to transfer it into the patient’s body and hold it in the spot. There used to be many candidates, but they can only function at small ranges of pH outside your body. Now you must be confused; what exactly is pH? Well, think of a pool of sticky bubble gums. These gums are called H. When the pH is low, there are a lot of gums in the pool, so when the claw enters the pool, the gum will stick onto the claw, now the claw surface becomes soft, and the Germanium just slips away. Unfortunately, the human body is such a low pH pool. No claw has been able to hold the playful Germanium under every condition. Surprisingly, Dr. Ovrig just made this new big claw in his lab that would hold onto the Germanium. When they tested it in different pools, even one similar to the human body, the Germanium stayed happily inside the claw. If you are curious about the name of this claw, it’s called Ga(hox).

 

The researchers then brought this claw into practice. They used the claw and germanium combination on a mouse, and it easily detected cancer monsters in the heart within a short 1 minute. The monsters in the liver and bladder are also exposed after 1 hour. Now, patients no longer have to worry about the long period of cancer examination. Besides, this technique can detect even tiny amounts of cancer monsters. Therefore, even in the very early stage of cancer, the claw-germanium combo can detect cancer and allow treatment before the cancer monster goes rampart.

Reference

Wang, X.; De Guadalupe Jaraquemada-Peláez, M.; Cao, Y.; Pan, J.; Lin, K. S.; Patrick, B. O.; Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals. Inorg. Chem. [Online] 2019, 58, 2275-2285. (Accessed: March 23, 2020).

Promoting Chemical Literacy in the Public

Responding to a need for scientific literacy in the public, researchers at the Samuel Neaman Institute examine ways to promote chemical literacy among different stakeholders.

The public increasingly encounters with real-life scientific and technological contexts, and scientific professional and chemical educators have realized the need for chemical literacy among the public to understand, and critically evaluate the scientific information they absorb. The University of British Columbia even offers a course, called CHEM 300, which teaches how to communicate scientific knowledge.

Broggan Textbook
(source: thriftbooks)

In an attempt to narrow the gap between the scientific and the non-scientific communities, researchers led by Zehavit Kohen conducted a comprehensive analysis of chemistry education methods most valued by different stakeholders.

The researchers identified four groups, K-12 students, teachers, scientists, and the educated public, from a sample population of 347. The survey divides into two sections, scientific literacy construction, and communication channel types.

According to the study, K-12 students valued cognitive and affective components twice more than scientists or educated adults. Besides, all stakeholders favored open discussions as their communication channel. Mass media dominates the scientific community besides open discussions. Whereas, students use mass media, be available to the public, and share of scientific materials indistinguishably.

Mass Media
(Source: flickr)

Investigating question posts on an ask-a-scientist-type website, the research further discovered that the public’s questions usually concern symbols over processes or systems. The type of information involved in these questions is mostly explanatory.

Data from Zehavit’s article

The results encourage students to gain chemical literacy in real-world contexts through analogies and symbols. The researchers also suggest that scientists should attempt other communication channels since interactive and affective activities on mass media are often challenging.

 

Reference

Zehavit, K.; Orit, H.; Yehudit J. D. How to promote chemical literacy? On-line question posing and communicating with scientists. Chem. Educ. Res. Pract., 2020, 21, 250

Making Different Sugars with Enzyme (Pac-Man) In Our Body

Although eating too much sugar can lead to health complications, a normal intake of sugar has its benefits. This is because sugars take part not only in many cellular activities as an energy source but also in cell-cell communication as a communicator. In 2019, a research team led by Dr. Stephen Withers at the University of British Columbia made different sugars by using enzymes (Pac-Man-like molecules) in bacteria. This finding enables the building of many sugars that are commonly hard to find in nature.

What are sugars?

All sugars are made of hexagonal building blocks as shown in red in Figure 1. Two common building blocks are glucose and fructose. To make different sugars with only two common building blocks, we can vary the number and arrangement of the building blocks. For example, cellulose has three long threads that are arranged almost parallel to each other. In contrast, starch has one long thread that adopts a helical structure.

Now we know that different sugars can be made by varying the kinds of building blocks, the numbers of building blocks and the arrangements of building blocks. What we haven’t talked about is how the building blocks are linked. There are two issues with linking the building blocks. First, building blocks are much smaller than our cells. Getting two building blocks together is as hard as fishing a needle from the Pacific Ocean. Besides, getting two building blocks together takes time because they prefer to be alone. How can our mother nature solve these problems to keep us alive?

Figure 1. Sugars are built differently. Some sugars are longer and more complex than others. Source: riasparklebiochemistry

Here comes the rescue…Pac-Man in the cells!

The illustrations of enzymes are like Pac-Man. However, different from Pac-Man that eats any “food” in different shapes, enzymes recognize different substrates and those substrates only! Because of this substrate-enzyme specificity, linking two building blocks together is much easier. As shown in Figure 2, the enzyme will attract two specific building blocks, making them closer to each other and eventually join.

Figure 2. Different enzymes recognize different substrates. Source: Wikipedia

Besides, enzymes can speed up the “hugging” process between the substrates (building blocks), making the formation of a long sugar favorable.

Figure 3. Enzymes speed up reactions. Source: pinimg.com

Manipulation of enzymes to build different sugars for cell-cell communication

Knowing that enzymes have many advantages, Dr. Wither and his team looked for enzymes that speed up the linkage of sugar building blocks in E. Coli, bacteria that live inside our digestive tracts. They chose eight enzymes out of the 175 sugar-specific enzymes in E. Coli. These eight enzymes were the most specific to the sugar building blocks they were interested in. However, after further investigation, the researchers found that the enzymes helped speed up the breakage of the linkage(s) between sugar building blocks instead of the formation of the linkage(s).

Figure 4. Some enzymes speed up the breakage of linkages while others speed up the formation of linkages.
Source: Canstock.com

To solve this problem, the researchers reverse-engineered these enzymes from speeding up breakage to speeding up linkage by changing parts of the enzymes. Now different sugars can be made! As mentioned above, cell-cell communication relies on sugars. This is because two cells adhere via the interaction between extracellular sugars and specific cell-surface receptors. Once these cells adhered to each other, they can talk to each other about their internal cellular condition/environment and trigger a corresponding response. This has great implications in triggering an immune response to a viral attack. By engineering more sugars on the surface of the cells, cells in our immune system can more quickly talk to each other and fight off infection.

 

Journal 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.

-Pricia Ouyang

A Novel Molecule for Nuclear Medicine

Cancer is complicated, there’s no doubt about that. From its onset to its invasive prevalence, preventing the progression of each stage seems like a never-ending battle. Be that as it may, with the advent of new chemical entities, this fight has become a lot easier.

In 2019, the Orvig group in the University of British Columbia were able to design and create a new molecule with a variety of applications. One of which is in cancer imaging, which is what makes their compound particularly astonishing. Further, the authors have reported that their chemical species is stable in, and is removed quite easily from the body. Though to understand the importance of their findings, it is vital to start at the very beginning.

Dr. Orvig (Top row, left) and his medicinal inorganic chemistry group

Within the realm of diagnostic medicine, imaging is a vital facet. The goal of imaging is to ultimately produce a viable image of the body. Positron emission tomography (PET) is an imaging method used to generate images of the chemical changes that happen in tissue. These scans often rely on the properties of the radiation emitted by a radioactive isotope. In this instance, the radioisotope used is Gallium-68 (68Ga), which is a readily available and versatile tracer species. Though, to harness the tracer capabilities of 68Ga, it would have to exist in the form of a compound. This is where the Orvig group plays an important role.

They were able to synthesize a ligand with the ability to interact with the 68Ga. A ligand is essentially a molecule that can bind to a metal center, forming a metal complex. This leads to the generation of a stable species that can exist in solution and thus can move around the body. What the group was able to show was that this novel ligand had a high affinity for 68Ga even at low concentrations. Their ligand is an acyclic hexadentate ligand, named H2hox. Though the name is inherently complicated, it does make sense once it is explained in some depth.

The Orvig group’s hexadentate chelating ligand

A hexadentate ligand is a ligand that coordinates to the metal center at 6 different positions. What this means is that there are 6 different points on the one molecule that bond with the metal center. Furthermore, the ligand is said to chelate the metal center. This term is generally given to a ligand that binds to a central metal atom at two or more points. Fortunately, this ligand is advantageous in a number of different ways.

The authors have stated that this compound is easy to synthesize, removing a number of potentially challenging synthetic strategies typically associated with 68Ga chelating species. Their initial starting materials were also inexpensive and are actually available online. To put this into perspective relative to some of the other ligand synthesis methods, 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 chelating ligand. Fortunately, their synthesis strategy is also mild.

What was also found is that their ligand is more stable than other 68Ga chelating ligand species. One advantage reported is with respect to acids and bases, where it was found that the complex is actually stable in both. It was found that there exists a single species, [68Ga(H2hox)]+, within a pH range of 1-11. Moreover, the group assessed the conditional stability of the complex. Again, these findings reinforce the advantages of their chelating ligand, H2hox.

Stability studies conducted in the sternum of mice and dynamic imaging PET studies also suggest that their compound is stable in the body and in a vial. This impressive aspect correlates with the enhanced stability of the H2hox metal complex. It was also removed from the mouse relatively quickly.

As a result of their success, their chelating species surpasses any ligand currently used as a 68Ga chelator. Not only have they managed to add to the current library of chelators, but they have also developed a convenient toolkit radiopharmaceutical compound.

Reference:

Wang, X.; De Guadalupe Jaraquemada-Peláez, M.; Cao, Y.; Pan, J.; Lin, K. S.; Patrick, B. O.; Orvig, C. H2hox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for 68Ga Radiopharmaceuticals. Inorg. Chem. [Online] 2019, 58, 2275-2285. (Accessed: March 23, 2020).

https://pubs.acs.org/doi/abs/10.1021/acs.inorgchem.8b01208

– Akash Panjabi

Bacteria: Friend or Foe?

Did you know that not all bacteria is bad? In some cases, they cause diarrhea, stomach ulcers, and even intestinal diseases. However, what if I told you scientists have found a way to manufacture antibiotics that are used to treat these bacterial infections from bacteria themselves?

Scanning Electron Microscope view of bacteria. Retrieved from: NYTIMES

Dr. Jason Hedges and Dr. Katherine Ryan of the University of British Columbia took a look into finding new enzymatic pathways for synthesizing nitroimidazole, which is a component in the antibiotic, azomycin.

So what is the point of this whole process and why do we even want to use bacteria to synthesize antibiotics?

By finding more ways to develop antibiotics from bacteria, this improves our knowledge on biosynthetic pathways. This is beneficial not only for the scientific community, but for the public as well. As bacteria develop resistances to antibiotics over time, the discovery of new antibiotics would be able to treat more patients suffering from bacterial infections.

How is this done?

Now how could something that sounds so complex be done? Let us take a look at their process step-by-step.

Like all scientists do, background research was performed to see how previous scientists went about finding ways to develop antibiotics from bacteria. To do so, a bioinformatics search was performed. Bioinformatics is essentially ‘googling’ information about a certain topic, but in this case, they would be using a scientific database such as the National Centre for Biotechnology Information (NCBI).

A cryptic gene cluster was found in the bacterial strain Streptomyces cattleya. This along with various enzymes were the main points of interest. Their goal was to use L-arginine; a fundamental building block of proteins, and find a way to convert this into nitroimizadole (a component of the antibiotic, azomycin

Theoretically, a blueprint on how L-arginine would be converted to nitroimidazole was developed. However, experiments must be conducted to see if the pathway would work in real life, and not just on paper.

Figure 1 – Biosynthetic pathway towards nitroimidazole. Retrieved from: Hedges and Ryan, 2019

Through experimentation, the pathway as shown in figure 1 was deemed to have synthesized nitroimidazole successfully. The next step was to determine whether or not azomycin could be synthesized from Streptomyces cattleya. Unfortunately, they were unsuccessful in detecting any levels of nitroimidazole in the bacteria samples. They concluded that potentially a different molecule had been synthesized, or that this specific gene cluster is silent (inactivate).

Although Hedges and Ryan were unable to find a definitive pathway to synthesizing azomycin utilizing bacteria, their work was able to disprove aa few reaction schemes in the scientific community, allowing for further research to be conducted.

Science is not always about success. In science, you must fail in order to succeed. Their work provides a stepping stone into further scientific research such a finding other biosynthetic pathways in the synthesis of other antibiotics.

 

Literature Cited:

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.

-Jackson Kuan