Journal Article

Evolutionary stability of collateral sensitivity to antibiotics in the model pathogen Pseudomonas aeruginosa

Römhild, Roderich, Barbosa, Camilo, Schulenburg, Hinrich, Rosenstiel, Philip

2019

Overview

Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus account for the adaptive potential of pathogens. One option is to exploit evolutionary trade-offs, like collateral sensitivity, where evolved resistance to one antibiotic causes hypersensitivity to another one. To date, the evolutionary stability and thus clinical utility of this trade-off is unclear. We performed a critical experimental test on this key requirement, using evolution experiments with Pseudomonas aeruginosa, and identified three main outcomes: (i) bacteria commonly failed to counter hypersensitivity and went extinct; (ii) hypersensitivity sometimes converted into multidrug resistance; and (iii) resistance gains frequently caused re-sensitization to the previous drug, thereby maintaining the trade-off. Drug order affected the evolutionary outcome, most likely due to variation in the effect size of collateral sensitivity, epistasis among adaptive mutations, and fitness costs. Our finding of robust genetic trade-offs and drug-order effects can guide design of evolution-informed antibiotic therapy. Over time bacteria can undergo a number of genetic mutations that allow them to evolve in response to changes in their surrounding environment. This process of ‘bacterial evolution’ is one of the major causes of antibiotics resistance, whereby disease-causing microorganisms become resistant to multiple drugs and can no longer be destroyed using antibiotic treatment. However, when bacteria become resistant to a drug this can result in an evolutionary trade-off known as ‘collateral sensitivity’ – when evolving resistance to one drug causes bacteria to gain increased sensitivity to another. Now, Barbosa, Roemhild et al. have investigated whether this evolutionary trade-off could be exploited to tackle the antibiotic crisis and prevent bacteria adapting to different treatments. If this evolutionary trade-off is to be used medically, it must be stable long enough for the bacteria population to either become extinct, or less able to evolve multi-drug resistance. To test how stable collateral sensitivity is over time, Barbosa, Roemhild et al. studied the bacterium Pseudomonas aeruginosa which is known to evolve collateral sensitivity to certain drug treatments. P. aeruginosa were subjected to two rounds of evolution: first, bacteria were evolved to resist ‘Drug A’ and at the same time became more sensitive to another drug, ‘Drug B’. The bacteria were then allowed to adapt to Drug B either alone or in the presence of Drug A. These evolutionary experiments revealed that the following factors affected the stability of the trade-off: the molecular structure of the antibiotic bacteria evolved sensitivity to, the strength of the original evolutionary trade-off (i.e. how sensitive bacteria became), the order drugs were administrated, and whether resistance came at a large fitness cost (i.e. when the genetic mutations promoting resistance affect bacteria’s ability to replicate and survive in normal conditions). According to the World Health Organization, P. aeruginosa is the second most problematic multi-drug resistant bacteria. The data collected in this study could therefore be used to develop a new antibiotic therapeutic strategy for fighting this bacterium, as well as other microbes which are resistant to multiple drugs.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications, Ltd,eLife Sciences Publications Ltd
• Subject: Anti-Bacterial Agents - pharmacology / antibiotic therapy / Antibiotics / Bacteria / Biological Evolution / collateral sensitivity / Drug resistance / Drug Resistance, Multiple, Bacterial - drug effects / Epistasis, Genetic - drug effects / Evolution (Biology) / Evolutionary Biology / Gene mutation / Genome, Bacterial / Microbial drug resistance / Microbiology and Infectious Disease / Microorganisms / Models, Biological / Mutation - genetics / Pathogenic microorganisms / Pharmaceutical industry / Pseudomonas aeruginosa / Pseudomonas aeruginosa - drug effects / Pseudomonas aeruginosa - genetics / Public health / sequential therapy / World health