Antibiotic-Induced Morphological Changes Enhance Phage Predation: A Mathematical Model of Plaque Formation in Structured Environments

Abstract

A distinctive manifestation of phage infection in solid media is the appearance of lysis plaques, corresponding to the circular thinning of a bacterial lawn. During plaque formation, successive cycles of phage replication take place from a single point of infection and spread radially in a matrix of immobilized bacterial hosts. Many factors affect plaque size, such as the composition and the reticulation of the propagation matrix, the characteristics of the phage, but also parameters related to the physiology of the bacterial host. As the combined administration of antibiotics and phages is a common practice in compassionate treatments, our research focuses on the effects of antibiotics on phage predation, which may be of crucial importance for phage therapeutic applications. Sublethal concentrations can drastically affect bacterial physiology, allowing phages to spread more rapidly and resulting in better bacterial eradication. Previous experimental work has focused on the phage characteristics. However, as plaque formation is strongly influenced by host growth dynamics, a comprehensive model integrating both the host growth and phage infection parameters is required. We suggest that plaque enlargement is linked to morphological changes of the host that have an impact on the rate of epidemic propagation and on phage diffusion into the matrix. To support this hypothesis, we characterized the growth parameters of two different phages and bacteria in semi-solid media in the presence of various antibiotics. By combining these data, we have produced a mathematical model that accounts for these observations and explains the increase in plaque size when the host morphology is affected.