An evolutionary outlook on antibiotic resistance

Craig MacLean discusses his groups research into antibiotic resistance for the Trinity Term 2021 Alumni Newsletter.

For most of human history, bacterial pathogens have been a leading cause of disease and death. The discovery of penicillin provided a simple and effective way to treat bacterial infections, and antibiotics were initially hailed as a ‘silver bullet’ that would effectively eradicate bacterial disease. Against this backdrop of unbounded optimism, Alexander Fleming warned that the overuse of antibiotics would lead to the rise of resistance in his 1945 Nobel Prize acceptance speech. Remarkably, very little attention was given to Fleming’s warnings, and penicillin resistant strains of the pathogen Staphylococcus aureus began to spread epidemically in the 1950s.

The 20th century solution to resistance was to use novel antibiotics to treat infections caused by resistant strains. However, the rate of discovery of new antibiotics has declined over time, and the prevalence of multi-drug resistance in pathogenic bacteria has increased. Infections caused by antibiotic resistant bacteria currently cause over 1 million deaths per year, and an influential report published by the O’Neill commission in 2016 predicts that resistant infections will cause 10 million deaths per year by 2050. Whilst these figures are still under debate, this landmark report highlighted the current and future risk of antibiotic resistance. It is clear that new antibiotics are needed, but the past has shown us that new drugs alone will not provide a sustainable solution to this crisis.

My research group uses evolutionary approaches to understand the drivers of resistance and to develop ‘evolution-guided’ principles for combatting resistance. Treating bacterial populations with antibiotics damages and kills bacteria, generating a selective advantage for cells that are protected against antibiotics by resistance genes. The growth of resistant populations can cause infections to relapse, and it provides the opportunity for resistance to transmit between hosts. Whilst the logic of this evolutionary model of resistance is simple, this idealized sketch leaves out a huge amount of important biological detail.

For example, it is challenging to apply conventional evolutionary models that are based on mutation to antibiotic resistance, because most resistance genes are found on plasmids that can transfer between bacterial strains and species. Our work has shown that in order to understand the drivers of mobile resistance, we need to think about antibiotic resistance at the scale of bacterial communities and take into account the potential for co-evolution between plasmids and their bacterial hosts. Genomic sequencing of pathogenic bacteria is increasing at a staggering rate, and it is now clear that most pathogen species are incredibly diverse at a genetic level. Our work has identifed genes that make some bacterial strains more evolvable than others by opening up new genetic routes to resistance. Importantly, understanding the link between genetic architecture and evolvability can be used to optimize antibiotic treatment strategies.

This is an exciting time to be working on antibiotic resistance in Oxford. Applying concepts from evolution and ecology is providing new insights into the processes that drive resistance, and new initiatives, such as the Ineos Oxford Institute, are paving the way for transforming these advances into solutions for the resistance crisis.