Introduction
Antibiotic resistance and metabolic modelling
A digital story by Maxime Mahout.
PhD Student, LISN, Université Paris-Saclay.
PhD Student, LISN, Université Paris-Saclay.
At Alfred's hospital
Alfred is a doctor working at his hospital.
He is specializing in intensive care.
Today’s cases of wound infections are particularly
difficult.
The main cause?
Two main bacteria, Pseudomonas aeruginosa and Staphylococcus aureus. These two bacteria are very infectious and particularly resistant to antibiotics.
Two main bacteria, Pseudomonas aeruginosa and Staphylococcus aureus. These two bacteria are very infectious and particularly resistant to antibiotics.
Antibiotic resistance
The dangers of antibiotic resistance
Antibiotic resistance is a great danger to human and environment health. The number of bacterial infections becoming harder to treat is ever growing, and these affect all life areas, including food safety.
Meanwhile we keep overusing antibiotics and involuntarily allowing deadly bacteria strains to be genetically selected.
A major risk linked to antibiotic resistance would be the rise of an era without protection by our current antibiotics.
Meanwhile we keep overusing antibiotics and involuntarily allowing deadly bacteria strains to be genetically selected.
A major risk linked to antibiotic resistance would be the rise of an era without protection by our current antibiotics.
Antibiotics get overused
As an example, the deadliest strains of
Staphylococcus aureus are now becoming resistant to the
Methicilin antibiotic (first strain discovered in
1961) and to the Vancomycin antibiotic (first
strain discovered in 1996).
In hospitals such as Alfred’s, to avoid overuse of antibiotics, administration of antibiotics to patients is decided on a case-by-case basis.
In hospitals such as Alfred’s, to avoid overuse of antibiotics, administration of antibiotics to patients is decided on a case-by-case basis.
Bertille's lab
Biofilms are harder to treat
Pseudomonas aeruginosa and Staphylococcus
aureus are commonly found forming biofilms in
infections of patient wounds.
It is harder to treat these two bacteria together in
the same biofilms as they have very different
particularities.
This is a result of the cooperation of the bacteria:
they genetically evolved to cooperate and to resist
human healthcare.
Confronted with this situation, Alfred decides he should call his younger biologist collaborator, Bertille.
Confronted with this situation, Alfred decides he should call his younger biologist collaborator, Bertille.
Alfred calls Bertille
Alfred: “Bertille, how have you been?”
Bertille: “Oh Alfred, I’ve been great! Are you still working on raising funds for our collaboration project?”
Alfred: “Yes, of course, it’s almost done. In fact, I am calling you because today has been a terrible day. We almost lost a patient to a wound infection.”
Bertille: “Oh, that’s awful. I’ll make sure to prepare the paperwork on my end.”
Bertille studies metabolism interactions between bacteria, a topic Alfred had not considered until recently.
Bertille: “Oh Alfred, I’ve been great! Are you still working on raising funds for our collaboration project?”
Alfred: “Yes, of course, it’s almost done. In fact, I am calling you because today has been a terrible day. We almost lost a patient to a wound infection.”
Bertille: “Oh, that’s awful. I’ll make sure to prepare the paperwork on my end.”
Bertille studies metabolism interactions between bacteria, a topic Alfred had not considered until recently.
Bacterial interactions
Bertille has been working with bacterial metabolism
interactions for 3 years.
Bacteria like Pseudomonas aeruginosa and Staphylococcus aureus take part in a process called cross-feeding.
It is a symbiotic relationship: the first bacteria profits from the nutrients produced by the other bacteria.
In general, metabolism interactions between bacteria are difficult to study.
Indeed, when the bacteria are cultivated together, Bertille is unable to distinguish which is which without microscope.
Bacteria like Pseudomonas aeruginosa and Staphylococcus aureus take part in a process called cross-feeding.
It is a symbiotic relationship: the first bacteria profits from the nutrients produced by the other bacteria.
In general, metabolism interactions between bacteria are difficult to study.
Indeed, when the bacteria are cultivated together, Bertille is unable to distinguish which is which without microscope.
Bacteria are tedious to work with
Tired of not understanding the bacteria, Bertille
discovered the field of modelling.
She decides she could make a computer model to avoid the struggle of cultivating real bacteria!
This involves her computer scientist friend, Joël.
She decides she could make a computer model to avoid the struggle of cultivating real bacteria!
This involves her computer scientist friend, Joël.
Joel's lab
At Joël's lab
Joël: “Oh Bertille, you are finally here.”
Bertille: “Yes, it is a good thing our labs are close to each other.”
Joël: “Is the project with the hospital going well?”
Bertille: “Yes. In fact, I had my doctor collaborator, Alfred, at the phone yesterday.”
Bertille: “Yes, it is a good thing our labs are close to each other.”
Joël: “Is the project with the hospital going well?”
Bertille: “Yes. In fact, I had my doctor collaborator, Alfred, at the phone yesterday.”
Bacterial computer models
Originally a computer scientist only,
Joël
was one
day introduced to computer models of bacterial
cells.
A computer model of a bacteria behaves just like the real bacteria, but without having to do the experiments!
This makes it easier, cheaper and safer to make discoveries, especially on bacteria that are known to be pathogenous!
A computer model of a bacteria behaves just like the real bacteria, but without having to do the experiments!
This makes it easier, cheaper and safer to make discoveries, especially on bacteria that are known to be pathogenous!
Metabolic modelling
However, Joël knows nothing about biology, so he
constructed the model together with Bertille.
Joël learned that metabolism is the set of chemical reactions essential to a cell’s survival.
A computer model of the metabolism of a cell is called a metabolic model.
Joël learned that metabolism is the set of chemical reactions essential to a cell’s survival.
A computer model of the metabolism of a cell is called a metabolic model.
Downloading from Internet databases
Joël compiled the set of reactions known to occur
in each bacterium available from Internet databases.
He obtained metabolic models of Pseudomonas aeruginosa and Staphylococcus aureus! Bertille was really impressed at this feat, she wouldn’t have thought everything was already readily available in a database!
Bertille: “Wow, constructing the model was so fast!”
Joël: “Yes! It was automated so I’m not sure how well it works though!”
Bertille: “Let me test it then.”
He obtained metabolic models of Pseudomonas aeruginosa and Staphylococcus aureus! Bertille was really impressed at this feat, she wouldn’t have thought everything was already readily available in a database!
Bertille: “Wow, constructing the model was so fast!”
Joël: “Yes! It was automated so I’m not sure how well it works though!”
Bertille: “Let me test it then.”
Playing with the models
Now with two computer-generated bacteria models, Joël and Bertille can simulate what could happen in experimental conditions.
They grow the two fake bacteria with the same food. They observe that the bacteria produce different compounds.
But some of the compounds produced by Pseudomonas aeruginosa can be consumed by Staphylococcus aureus.
And alternatively, some other compounds produced reduce the growth of Staphylococcus aureus.
They simulate even more, changing the compound quantities, removing some genes and reactions.
They grow the two fake bacteria with the same food. They observe that the bacteria produce different compounds.
But some of the compounds produced by Pseudomonas aeruginosa can be consumed by Staphylococcus aureus.
And alternatively, some other compounds produced reduce the growth of Staphylococcus aureus.
They simulate even more, changing the compound quantities, removing some genes and reactions.
Concluding thoughts
Back at the hospital
Joël and Bertille report their many results to Alfred.
They hope that their computer predictions can lead to therapeutic solutions for Alfred’s patients!
Alfred is very thankful to them.
Alfred: “Thank you two for your work! I learned a lot about how to better treat my patients.”
Joël & Bertille: “It was a pleasure!”
They hope that their computer predictions can lead to therapeutic solutions for Alfred’s patients!
Alfred is very thankful to them.
Alfred: “Thank you two for your work! I learned a lot about how to better treat my patients.”
Joël & Bertille: “It was a pleasure!”
Concluding remarksWhy metabolic modeling?
Modeling in biology starts from a simple principle: to understand how living cells work, we must first be able to make computer models based of our knowledge of the subject.
It is still a relatively new field which requires collaborative and interdisciplinary work and where a lot is yet to be discovered.
Joël and Bertille might not find something that helps Alfred’s patients right away, but any advance in their studies may be useful to the whole biology research community.
It is still a relatively new field which requires collaborative and interdisciplinary work and where a lot is yet to be discovered.
Joël and Bertille might not find something that helps Alfred’s patients right away, but any advance in their studies may be useful to the whole biology research community.
End
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Copyright
Pexels, Pixabay (All rights reserved)
Public domain, CC0 images from Wikimedia Commons
File:Mixed-culture biofilm.jpg - Wikimedia Commons (CC BY, AI-Upscaled)
Figures by Maxime Mahout.
Public domain, CC0 images from Wikimedia Commons
File:Mixed-culture biofilm.jpg - Wikimedia Commons (CC BY, AI-Upscaled)
Figures by Maxime Mahout.
References
[1] Antimicrobial Resistance Collaborators. "Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis", The Lancet 2022.
[2] P. C. Appelbaum. "The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus". Clinical Microbiology and Infection, 2006.
[3] Yang et al. "Pattern differentiation in co-culture biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa". FEMS Immunology and Medical Microbiology, 2011.
[4] Jeremy S. Edwards, Markus Covert and Bernhard Palsson.
"Metabolic modelling of microbes: the flux-balance approach". Environmental Microbiology, 2002.
[2] P. C. Appelbaum. "The emergence of vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus". Clinical Microbiology and Infection, 2006.
[3] Yang et al. "Pattern differentiation in co-culture biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa". FEMS Immunology and Medical Microbiology, 2011.
[4] Jeremy S. Edwards, Markus Covert and Bernhard Palsson.
"Metabolic modelling of microbes: the flux-balance approach". Environmental Microbiology, 2002.
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Antibiotic resistance and metabolic modelling
The dangers of antibiotic resistance
Antibiotics get overused
Biofilms are harder to treat
Bacterial interactions
Bacteria are tedious to work with
Bacterial computer models
Metabolic modelling
Downloading from Internet databases
Playing with the models
Back at the hospital
Concluding remarks
Review previous chapters?
