Interactions with a phage gene underlie costs of a β-lactamase

Abstract

AbstractThe fitness cost of an antibiotic resistance gene (ARG) can differ across host strains creating refuges that allow maintenance of an ARG in the absence of direct selection for its resistance phenotype. Despite the importance of such ARG-host interactions for predicting ARG dynamics, the basis of ARG fitness costs and their variability between hosts are not well understood. We determined the genetic basis of a host-dependent cost of a β-lactamase,blaTEM-116*, that conferred a significant cost in oneEscherichia colistrain but was close to neutral in 11 otherEscherichia spp.strains. Selection of ablaTEM-116*encoding plasmid in the strain in which it initially had a high cost resulted in rapid and parallel compensation to that cost through mutations in a P1 phage gene,relAP1. When the wildtyperelAP1gene was added to a strain in which it was not present and in whichblaTEM-116*was neutral, it caused the ARG to become costly. Thus,relAP1is both necessary and sufficient to explainblaTEM-116*costs in at least some host backgrounds. To our knowledge, these findings represent the first demonstrated case of the cost of an ARG being influenced by a genetic interaction with a phage gene. The interaction between a phage gene and a plasmid-borne ARG highlights the complexity of selective forces determining the maintenance and spread of ARGs, and, by extension, encoding phage and plasmids, in natural bacterial communities.