Abstract The spread of mobile genetic elements (MGEs) through horizontal gene transfer (HGT) can influence the dynamics, function, and survival of microbial communities. A major mechanism of HGT, conjugation, plays a critical role in the acquisition and spread of antibiotic resistance in pathogenic bacteria. By combining high- throughput phenotypic quantification and genomic sequencing, we recently showed that >25% of >200 clinical bacterial isolates expressing extended spectrum ß-lactamases (ESBLs) can effectively transfer their resistance through conjugation. The widespread of transferable plasmids raises fundamental questions regarding the determinants of their persistence and how it can be reversed. Past studies have established that the persistence of a plasmid depends on two critical traits – the fitness effect of the plasmid and its transfer rate. In preliminary work, we discovered a robust threshold-linear correlation between plasmid burden and conjugation efficiency. Most of the plasmids do not experience a significant increase in burden unless their conjugation efficiency reaches a threshold. Beyond the threshold, a significant tradeoff emerges between the two aspects: the faster a plasmid transfer, the greater the burden it causes to the host. This tradeoff has implications for the persistence and evolution of plasmids in microbial communities. Building on the foundation of our published work and the preliminary results, the central goal of the proposed research is to examine this quantitative correlation in terms of its underlying molecular mechanisms and its general applicability (different plasmids, bacterial hosts, and growth environments). We will also investigate the ecological and evolutionary consequences. To achieve this goal, we will quantify this correlation for a broad spectrum of transferable plasmids in different bacterial hosts, examine the expression patterns of genes associated with plasmids and hosts using sequencing, and predict and measure persistence of these plasmids under different experimental conditions. The proposed research will generate unprecedented, quantitative measurements of modulation of HGT by antibiotics and other environmental factors.