Differentiation Between Regulated and Disrupted Growth Arrests Allows Tailoring of Effective Treatments for Antibiotic Persistence

Antibiotic persistence, typically attributed to dormant bacteria, is known to be a major cause of treatment failure. However, despite many years of intense research, no clear consensus on its mechanism has emerged. Here, we demonstrate that high survival under antibiotics may originate from two fundamentally different growth-arrest archetypes: either from a regulated growth arrest, leading to a protected dormant cellular state, or from a dys-regulated disrupted growth arrest. Using modeling and experimental approaches including transcriptomics, microcalorimetry, and microfluidics, we unveil the characteristics and vulnerabilities of each growth-arrest archetype. In particular, disrupted bacteria show a general impairment of membrane homeostasis. This understanding resolves previous conflicting results regarding characteristics of persisters and allows tailoring treatments that target the different growth-arrested bacteria. The fundamental distinction between regulated and disrupted growth arrests should be broadly relevant for the description of cells under stress.