Tag Archives: antibiotics

The Key to Treating Pneumonia can be Found in Soil?

Posted on March 27, 2020 by | Leave a comment

Can it really be that simple? Can the answer really be in the ground beneath our feet?

Source: Soil Science Society of America

Discovery of a gene cluster commonly found in soil-dwelling bacteria may be the key to treating anaerobic bacterial infections such as appendicitis and pneumonia. Researchers Jason B. Hedges and Prof. Dr. Katherine S. Ryan from the University of British Columbia have isolated the antibiotic compound azomycin from a biosynthetic gene cluster found in the bacterium Streptomyces cattleya.

With this information they believe it can lead to engineering bacteria to produce a new line of antibiotics.

What is a gene cluster?

The term gene cluster is moreso semantics to describe a group of genes that share a common phenomenon.

Originally, azomycin was isolated from a similar bacterium Streptomyces eurocidicus back in 1953 and became the blueprint to synthetic nitroimidazoles. 

“Nitroimidazoles are one of the most effective ways to treat anaerobic bacterial infections”,[1] Hedges writes in his 2019 study. The most commonly used nitroimidazole, metronidazole, is an antibiotic used to treat pelvic inflammatory disease, endocarditis, and bacterial vaginosis.[2] It is also on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system.[3]

Figure 1: Molecular Structure of Nitroimidazole. Source: Sigma Aldrich

Despite its use in antibiotics for over 60 years, the incidence of nitroimidazole resistance in anaerobes remains low, making it an essential component of the antibiotic arsenal. [1,4]

Since the isolation of azomycin back in 1953, synthesis of nitroimidazoles were limited to synthetic routes, most commonly involving reactions of an imidazole with nitric acid and sulfuric acid. 

Using bioinformatics, however, in 2019 Hedges and Ryan were able identify a biosynthetic gene cluster in the same bacterium that makes penicillin,[5] Streptomyces cattleya. They were able to find that this gene cluster containing azomycin is widely distributed among soil-dwelling actinobacteria and proteobacteria.

Because of this they theorize that azomycin and other nitroimidazoles may be important factors in ecology.

What are bioinformatics?

Bioinformatics is the science of collecting and analyzing complex biological data such as genetic codes. As an interdisciplinary field of science, bioinformatics combines biology, computer science, information engineering, mathematics and statistics to analyze and interpret the biological data

In addition to the isolation of azomycin in a gene cluster, Hedges and Ryan were able to perform in vitro analysis in order to understand the enzymatic steps that take the primary protein L-arginine to become azomycin. 

Source: Washington Post

Their work opens the door to biocatalytic methods to synthesize azomycin and other nitroimidazoles. They believe this discovery can “lead to the possibility of engineering bacteria to produce nitroaromatic compounds”.[1]

In other words, this may lead to stronger antibiotics immune to drug resistance.

References

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.

The American Society of Health-System Pharmacists. Archived from the original on 6 September 2015. Retrieved 31 July 2015.

World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization

David I. Edwards, Nitroimidazole drugs-action and resistance mechanisms I. Mechanism of action, Journal of Antimicrobial Chemotherapy, Volume 31, Issue 1, January 1993, Pages 9–20, https://doi.org/10.1093/jac/31.1.9

Kahan, JS; Kahan, FM; Goegelman, R; Currie, SA; Jackson, M; Stapley, EO; Miller, TW; Miller, AK; Hendlin, D; Mochales, S; Hernandez, S; Woodruff, HB; Birnbaum, J (Jan 1979). “Thienamycin, a new beta-lactam antibiotic. I. Discovery, taxonomy, isolation and physical properties”. The Journal of Antibiotics. 32 (1): 1–12

-Adrian Emata

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Posted in Analytical Chemistry, Biological Chemistry, Chemistry News, Organic Chemistry, Popular Science

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Biosynthetic Pathway Found to Synthesize Anaerobic Antibiotics!

Posted on March 23, 2020 by | Leave a comment

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 2019, 58 (34), 11647–11651.

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Bacteria: Friend or Foe?

Posted on March 23, 2020 by | 1 comment

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 2019, 58 (34), 11647–11651.

-Jackson Kuan

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Antibiotics found to kill bacteria in a new way!

Posted on February 25, 2020 by | 4 comments

 

Fig1.Antibiotics source

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. On Feb 13th, 2020, Research team from the David Braley center for Antibiotic Discovery, University of McMaster posted an article on nature. Newly found corbomycin and complestatin would kill bacteria in a brand-new way. The discovery of these new groups of antibiotics would be the clinical candidate in the fight against antimicrobial resistance.

Fig2,Antibiotic resistance strategies in bacteria. source:Courtesy of E. Gullberg.

 

Antibiotics are the revolution of the pharmaceutical study in the 20th century. They are the most important type of antibacterial agent which either kills or inhibit the growth of bacterial cell walls. Alexander Fleming discovered modern antibiotic medicine – penicillin in 1928, which saved thousands of people’s life.

What does old antibiotics also bring you?

The enormous benefits of antibiotics also lead to new problems such as over-usage and resistance. Bacteria soon formed resistance toward these antibiotics and caused the ineffectiveness of the medicine. The resistance of antibiotics had become a new-rise problem. The World Health Organization announced: “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.”

Fig2.image of corbomycin

Fig2.image of corbomycin. source

The newly found corbomycin and complestatin have brand new way to attack bacteria. It is discovered from a glycopeptide family, and the new approach appears no significant resistance toward bacteria. “Antibiotics like penicillin kill bacteria by preventing the building of the wall, but the antibiotics that we found actually work by doing the opposite – they prevent the wall form being broken down. This is critical for cell to divide.” Said Beth Culp, a PhD candidate in biochemistry at McMaster.

Why do we know about these?

“We hypothesized that if the genes that made these antibiotics were different, maybe the way they killed the bacteria was also different”, Culp explained. The “unique approach” to kill bacteria is a new mechanism that is worthy of studying. Scientists might be able to find the new family of antibiotics which have a completely different way to attack bacteria. These new antibiotics will be the revolution of modern biochemistry which will be powerful to fight against antibiotic-resistant.

 

Scientists believed that the observation of corbomycin and complestatin would open the “new door” in the field of antibiotics. People will be able to investigate more antiobiotics to fight against resistance in the glycopeptide family. This study will eventually benefit thousands of people suffering in antibiotic-resistant and give them hope to survive!

–Vicky Gu

 

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