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Can antibiotic resistance be tested using a human organoid model?

 Microbes behave differently in the presence of human cells, and this can affect how susceptible they are to antimicrobials. What happens when we look at antimicrobial susceptibility in a more in vivo-like environment?

The ALI Model

 The Air-Liquid Interface (ALI) model is an effective way to study skin in the lab. Using a multi-well plate and ThinCert®, it is relatively easy to build up a complete skin section with all the relevant layers.
Crucially, this model can also produce an air-liquid interface that is characteristic of living skin. This model has been used to study the immune system and treatments for skin disorders, but what about using it to look at the microbiology of the skin?

A human skin infection, in the lab

Human skin is colonized by a wide range of microbes that interact with the human immune system regularly to maintain a healthy homeostasis. However, this balance becomes thrown off when we get a skin infection. It stands to reason that when we look for therapies to treat or prevent skin infection, we should consider them in the proper biological context, i.e., something that looks exactly like human skin.
This is possible using the ALI model. Pathogens and commensal microbes can be added to the cultured epidermis and an infection can be simulated. This means that any potential treatments can be evaluated in the context of human cells and the immune system. This is vital as we know that gene expression in vivo differs significantly from gene expression in vitro, meaning there is a high probability that bacterial cells will respond differently in vivo to antimicrobials.
When we stop studying infection in a vacuum and start using clinically-relevant approaches such as the ALI model, we start to see unexpected benefits. Using the ALI model with ThinCert®, a research team from Canada discovered a compound with three different beneficial effects during an infection (1).

3 beneficial antimicrobial effects uncovered with the ALI model 

Firstly, the compound killed bacteria. So far, so good, but this is a given for antimicrobials so what else could it do?

Well, the compound also irradicated biofilm which is a common feature of bacterial infections, especially on the skin. Bacteria congregate into biofilms that are more tolerant to antibiotics. By growing biofilms on their skin model, the researchers were able to strengthen their screening approach to find more clinically relevant antimicrobial compounds.

Thirdly, the researchers also found that the same compound that killed bacteria and irradicated biofilm could also modulate the innate immune response. This was only possible because the ALI model included immune cells found in the skin. The ability to modulate the immune response during an infection is a huge advantage for an antimicrobial drug as it can activate the immune system to start clearing the infection.

All this work was done on the methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, which is a dangerous isolate that is often found in hospital infections around the globe. The work using the ALI model helped to identify a new antimicrobial peptide that could help to kill MRSA in three different ways. This discovery was possible for two important reasons:
1.    The model closely represented the reality of an in vivo infection.
2.    The model was simple enough to perform screens of different compounds in the lab.
This combination of realism and simplicity is an important tool for antibiotic discovery and will inevitably help to accelerate the development of new treatments in the future.


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[1] )Hashem Etayash, Morgan Alford, Noushin Akhoundsadegh, Matthew Drayton, Suzana K. Straus, and Robert E. W. Hancock
Journal of Medicinal Chemistry 2021 64 (22), 16854-16863
DOI: 10.1021/acs.jmedchem.1c01712


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