The plasmid-host fitness landscape: a new paradigm for predicting the fate of mobile resistance

ABSTRACT The widespread persistence of antimicrobial resistance (AMR) plasmids presents a fundamental challenge to microbial evolution, known as the “plasmid paradox”: if these plasmids cause fitness cost, why are they not eliminated by selection? The classical view, which imposed a fixed generic fitness cost, is insufficient to explain their epidemiological success. Here, we propose a new paradigm—the plasmid-host fitness landscape—a multi-dimensional model that takes into account the complex interplay between ecology and genetics. This landscape unfolds into three main axes. First, the host axis reveals that fitness costs often arise from host-dependent genetic conflicts, not a generic burden. Second, the time axis demonstrates that the fitness cost of any plasmid can be negated over time through plasmid or chromosome compensations, which leads to ameliorating initial costs and locking in resistance. Third, the environmental axis shows that the fitness cost of any plasmid can be affected by external factors like temperature and sub-inhibitory concentrations of antibiotics. These factors dynamically modulate the benefits and costs of plasmid carriage. By integrating the complex interplay between these dimensions, we argue that the plasmid fitness costs are not a fixed generic measurement, but rather a contingent trajectory across this landscape. This paradigm shifts the focus from static measurements to a dynamic, predictive science, providing a new foundation for assessing and managing the threat of mobile resistance.