Timing of antibiotic administration determines the spread of plasmid-encoded antibiotic resistance during microbial range expansion

Abstract

The spread of antibiotic resistance (AR) is a major threat to global health. Plasmid-mediated horizontal gene transfer is the main mechanism by which AR is transferred between cells lying within close spatial proximity to each other. In this study, we address a fundamental question regarding the spread of AR-encoding plasmids: Is there an optimal time to administer antibiotics to minimize plasmid spread within microbial communities? We addressed this question using microbial consortia consisting of two Pseudomonas stutzeri strains, where one is an AR-encoding plasmid donor and the other a potential recipient. We allowed the strains to co-expand across a nutrient-amended surface and administered antibiotics at different points in time. We found that the extents of plasmid transfer and transconjugant proliferation have unimodal relationships with the timing of antibiotic administration, where they reach maxima at intermediate administration times. Using an individual-based model, we found that these unimodal relationships result from an interplay between the probability to acquire plasmids from neighboring cells and the probability of plasmid loss upon cell division. Our study provides novel mechanistic insights into the transfer and proliferation of AR-encoding plasmids within microbial communities and identifies the timing of antibiotic administration as an important determinant of AR spread.