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Antibiotic resistance driven by host immunity and rapid evolution

A new study published in Nature Communications recorded the work of an international team led by Oxford University scientists. The study reports that rapid bacterial evolution interacts with the host’s immunity to shape both the rise, and fall, of resistance during infection. It also emphasises the need for greater understanding of how our immune system works with antibiotics to suppress bacterial infections.

Antibiotic resistance poses a severe threat to human health. Causing over 750,000 deaths per year with an anticipated increase to 10 million deaths per year by 2050, resistant infections are shown to be rising at a significant rate. The treatment of patients with antibiotics is widely associated with the emergence of resistance and worse outcomes for patients. Although, the question of how resistance emerges during infections remains inadequately understood.

Co-author and Professor of Evolution and Microbiology at the University of Oxford, Craig MacLean, said: “Our study suggests that natural immunity can prevent resistance during infection and stop the transmission of restraint strains between patients. Exploiting this link could help us to develop new therapeutics to use against bacterial pathogens and to better use the antibiotics that we have now”.

The research is part of a larger ASPIRE-ICU study, which stands for ‘Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in EuRopE – Intensive Care Units’. Conducted by the COMBACTE consortium, the ASPIRE-ICU trial united multiple collaborators from leading academic research labs along with AstraZeneca scientists. The COMBACTE consortium is a major academia-industry collaboration investigating new approaches to antimicrobial resistance.

What was revealed in the study was that antibiotic treatment killed the overwhelming majority of bacteria causing the infection, but bacteria with resistant mutations continued to grow and replicate during treatment. However, they also discovered that the resistant mutants had low competitive ability, leading to the loss of resistance after treatment after treatment as resistant mutants were replaced by sensitive competitors that managed to escape the antibiotic treatment.

Professor Maclean said: “Both the rise and fall of resistance during infection are simple and elegant examples of evolution by natural selection”.

In its removal of around >90% of resistant mutants that were present at the start of antibiotic treatment, it was observed that host immunity helped to suppress much of the infection. It was also host immunity that eventually eliminated the resistant populations that were present after treatment.

These insights were procured by tracking changes in the bacterial population in a single subject at an unprecedented level of resolution and combining this with data on patient health and immune function. Pseudomonas aeruginosa was the bacterial pathogen in this case – it acts as an opportunistic pathogen that mainly causes infections in hospitalised patients and in people with cystic fibrosis or bronchiectasis.

Professor MacLean said: “This is the kind of study that I could have only dreamed of 10 years ago. Technological progress was certainly important to this project, but the real key to our success was increased collaboration and cross-talk between medical researchers and evolutionary biologists.”

Image: CDC via unsplash.com

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