Antibiotic misuse has resulted in the widespread emergence of antimicrobial resistance (AMR), which poses a substantial public health risk. This study sought to assess whether eliminating antibiotics could quickly lower the prevalence of AMR, with a focus on situations where resistance is transmitted by a single gene. Researchers investigated the mcr-1 gene in Escherichia coli, which confers resistance to colistin, a last-resort antibiotic. They hypothesized that the removal of antibiotics would lead to a swift reduction in resistance.
Methods:
- Model System: The study used the mcr-1 gene in Escherichia coli to model colistin resistance.
- Genetic Approach: A high-throughput reverse genetics method was employed to evaluate mcr-1 variants.
- Fitness and Resistance Measurement: The fitness cost and resistance levels were assessed by comparing the relative growth rates of 14,742 mcr-1 E. coli variants, including 3,449 single-nucleotide mutants, in colistin-free media and in media containing 2 μg/mL and 4 μg/mL colistin.
- Mutational Analysis: Costless resistant mutants were identified, and their properties were analyzed within the functional domains of mcr-1.
- Population Genetic Model: A simple population genetic model was constructed to predict the prevalence of mcr-1 in real-world scenarios, specifically analyzing data from China following the 2017 ban on colistin in fodder additives.
Key Findings:
- Fitness Cost: Wild-type mcr-1 incurred a significant fitness cost, with E. coli showing 73.8% less growth per 24 hours compared to a non-functional construct.
- Prevalence of Costly Mutants: 42.4% of mcr-1 mutants exhibited colistin resistance with significant fitness costs when grown under 4 μg/mL colistin selection.
- Rarity of Costless Mutants: Only 0.3% of mcr-1 mutants were costless and resistant, most of which had multiple mutations.
- Domain-Specific Mutations: Cost-reducing and resistance-enhancing mutations were enriched in the linker domain of mcr-1, while cost-increasing mutations were depleted.
- Population Genetics: The population genetics model accurately predicted the rapid decline in mcr-1 prevalence in real-world data following the colistin ban.
This study demonstrates that the removal of antibiotics can rapidly reduce AMR prevalence if the resistance gene incurs a high fitness cost and costless resistance is rare. The findings, based on the mcr-1 gene and colistin resistance, suggest that strategic antibiotic restriction could potentially reverse AMR in certain cases. This approach could be applied to other AMR genes, guiding public health strategies to manage and reduce antibiotic resistance effectively.
Link to the study : https://tinyurl.com/yr44te3h
