Antimicrobial resistance (AMR) is traditionally discussed in the context of horizontally acquired resistance genes and point mutations at target loci. However, this gene-centred model fails to account for a large number of clinically important modalities of resistance. There is now substantial evidence implicating bacteria in the ability to escape the effects of antibiotics in a variety of non-canonical ways, which are not considered in traditional diagnostic and surveillance pipelines. Among these factors, we can list those arising from global regulatory networks, phase variability, epigenetic tuning, small RNAs, genome structural variability, and phenotypic states like tolerance and persistence. This review will blend the current knowledge on these alternative pathways of resistance and underscore how they intersect with canonical genetic determinants. We will highlight cases where resistance emerges in the absence of known resistance genes, analyse the role of regulatory plasticity in efflux pump expression and membrane remodelling, and examine the contributions of bacterial stress responses and post-transcriptional control. Additionally, we will address methodological gaps in the detection of these mechanisms and their implications for clinical treatment failure, resistance surveillance, and drug development. By integrating insights from molecular microbiology, systems biology, and genomics, this review aims to offer a framework for understanding AMR as a multifaceted, context-dependent phenotype, not merely a genotype. We conclude by identifying knowledge gaps and suggesting priorities for research and diagnostic innovation in this evolving field.
Koolman et al. (Wed,) studied this question.