Bacterial protein post-translational modifications: a dynamic regulatory layer of antibiotic resistance

Antibiotic resistance has become a major threat to global public health. It is commonly explained by target mutations, acquisition of resistance genes, drug inactivation, enhanced efflux, and reduced permeability. However, even in an unchanged genetic background, bacterial susceptibility to antibiotics can shift rapidly with nutritional, metabolic, and stress states, indicating that the functional output of resistance determinants is also subject to post-translational regulation. Recent quantitative analyses of bacterial post-translational modifications (PTMs) have shown that PTMs can directly alter the charge, conformation, stability, localization, and interactions of pre-existing proteins, thereby rapidly modulating the functional output of classical resistance mechanisms without altering the underlying DNA sequence. Here, we reframe PTMs not as a standalone resistance mechanism but rather as a dynamic regulatory layer that modulates the strength and coordination of conventional resistance mechanisms. On this basis, we organize PTM-mediated resistance regulation into five interconnected modules distributed across three functional tiers. Within this framework, we further discuss combinatorial regulation by multiple PTMs and propose a resistance mechanism-based prioritization framework for PTM-targeted therapeutic strategies. We also identify site occupancy, temporal resolution, clinically relevant models, and multi-omics integration as key challenges for the next stage of the field. This framework helps distinguish causal PTMs from accompanying modifications and provides testable routes for translating PTM mechanisms into antibiotic resensitization strategies.