Heterogeneity in microbial antibiotic responses: genetic basis and within-host evolution

Antibiotic response phenotypes have traditionally been classified as either sensitive or resistant. However, accumulating evidence indicates that bacterial responses to antibiotics are far more heterogeneous than previously appreciated. A growing set of new descriptors—including antibiotic persistence, tolerance, heteroresistance, resilience, and perseverance—has been introduced to capture noncanonical antibiotic phenotypes, which are widespread in bacteria and recognized as a cause of treatment failure. Although defined by different criteria, these phenotypes all converge on the heterogeneous nature of bacterial antibiotic responses. In this review, we focus on the heterogeneity-causing mechanisms embedded in genome maintenance, transcription, and translation; discuss how within-host evolved mutations can modulate regulatory stochasticity and shift population dynamics in ways that favor bacterial propagation; and highlight key future directions.