Analysis of beta-lactam heteroresistance in CRE suggests a stage in the spectrum of antibiotic resistance

Abstract

Antibiotic resistance is a growing crisis that threatens many aspects of modern healthcare. Dogma is that resistance often develops due to acquisition of a resistance gene or mutation, and that when this occurs, all the cells in the bacterial population are phenotypically resistant which we term "homogenous resistance". In contrast, heteroresistance (HR) is a form of antibiotic resistance where only a subset of cells within a bacterial population are resistant to a given drug. These resistant cells can rapidly replicate in the presence of the antibiotic and cause treatment failures. If and how HR and homogenous resistance are related is unclear. Using carbapenem-resistant Enterobacterales (CRE), we show that HR to beta-lactams develops over years of antibiotic usage and that it is gradually supplanted by homogenous resistance. This suggests the possibility that HR may often develop before homogenous resistance and frequently be a stage in its progression, representing a major shift in our understanding of the evolution of antibiotic resistance.