Abstract
A better understanding of how antibiotic exposure impacts the evolution of resistance in bacterial populations is crucial for designing more sustainable treatment strategies. The conventional approach to this question is to measure the range of concentrations over which resistant strain(s) are selectively favored over a sensitive strain. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer. Using two Pseudomonas aeruginosa strains carrying resistance plasmids, we show that single resistant cells have <5% probability of detectable outgrowth at antibiotic concentrations as low as one-eighth of the resistant strain's minimum inhibitory concentration (MIC). This low probability of establishment is due to detrimental effects of antibiotics on resistant cells, coupled with the inherently stochastic nature of cell division and death on the single-cell level, which leads to loss of many nascent resistant lineages. Our findings suggest that moderate doses of antibiotics, well below the MIC of resistant strains, may effectively restrict de novo emergence of resistance even though they cannot clear already-large resistant populations.
Highlights
Antibiotics have had a huge impact on human health by reducing the burden associated with bacterial infections, and the use of antibiotics underpins many areas of medicine
A prominent concept is that preexisting resistant subpopulations will be selectively enriched within a particular range of antibiotic concentrations, an idea first proposed in the 1990s [10,11,12], refined by the definition of the “mutant prevention concentration” giving the upper bound of this range [13] and further developed into the “mutant selection window” (MSW) hypothesis [14,15,16]
Establishment of Resistance Is Inhibited by Sub-MIC of a resistant strain (MICR) Antibiotic Concentrations
Summary
Antibiotics have had a huge impact on human health by reducing the burden associated with bacterial infections, and the use of antibiotics underpins many areas of medicine. A prominent concept is that preexisting resistant subpopulations will be selectively enriched within a particular range of antibiotic concentrations, an idea first proposed in the 1990s [10,11,12], refined by the definition of the “mutant prevention concentration” giving the upper bound of this range [13] and further developed into the “mutant selection window” (MSW) hypothesis [14,15,16]. Resistance must stochastically arise in a sensitive cell by mutation, genomic instability
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