## 1 Introduction
In bacteria, such reprogramming constitutes a non-genetic, reversible, and often transient strategy aimed at optimizing bioenergetic resources and ensuring survival under hostile conditions, through the remodeling of key pathways such as glycolysis, the Krebs cycle, oxidative phosphorylation, lipid biosynthesis, and amino acid metabolism [12; 13; 14]. It is essential to distinguish this phenomenon from classical genetic resistance, which involves stable and heritable modifications in the bacterial genome [15]. The conceptual distinction between metabolic rewiring and genetic resistance is fundamental to understanding bacterial adaptation under antibiotic stress. While the former represents a dynamic, reversible survival strategy, the latter entails stable genetic changes that confer heritable resistance (Figure 1). These modifications include point mutations in antibiotic targets, acquisition of resistance genes via plasmids or transposons, and constitutive expression of inactivating enzymes or efflux pumps [16; 17]. Metabolic rewiring represents an adaptive phenotypic response, at times overlapping with the phenomenon of \"tolerance,\" in which bacteria temporarily survive antibiotic exposure without a corresponding change in the Minimum Inhibitory Concentration (MIC) [18; 19]. This state of reduced metabolic activity--typically associated with diminished reactive oxygen species (ROS) production, low respiration, and accumulation of toxic intermediates--has been shown to promote survival even in the absence of genetic alterations, as demonstrated in _Escherichia coli_ and _Staphylococcus aureus_[20; 21; 22]. Several studies have indicated that, under sublethal antibiotic pressure, bacteria can redirect carbon flux toward secondary pathways--such as the glyoxylate cycle--thereby reducing ROS generation and oxidative damage induced by quinolones or aminoglycosides [5; 7; 23]. This results in a transient form of metabolic resistance, which may nonetheless serve as a pre-mutational platform, facilitating the selection of bona fide genetic resistance events [24]. These mechanisms--the modulation of antibiotic uptake, the reduction in ROS production, and growth reprogramming--collectively define the functional basis of metabolic rewiring and its role in promoting bacterial tolerance (Figure 2). Figure 1: Comparative schematic of metabolic rewiring and genetic resistance in bacterial adaptation to antibiotic pressure. Metabolic rewiring is characterized by non-genetic, reversible, and transient changes that enable adaptive responses to environmental stress. In contrast, genetic resistance results from stable, heritable genetic modifications, such as mutations or horizontal gene transfer, that persist even in the absence of selective pressure. While metabolic rewiring supports immediate survival under stress, it may serve as a precursor to stable resistance by increasing the likelihood of mutation fixation. Image created using BioRender (accessed via web application, version as of May 2025), GraphPad Prism (version 10.1.2-2024), and PowerPoint (Microsoft 365, version 2404). At the molecular level, metabolic plasticity can interfere with antibiotic action through at least three mechanisms:  
* Modulation of antibiotic uptake: changes in membrane potential or lipid composition can reduce the entry of cationic antibiotics [25; 26]. * Reduction in ROS production: with significant consequences for the efficacy of bactericidal agents, whose activity depends on lethal oxidative stress [6; 27]. * Reprogramming of growth and division: cyclic arrest or metabolic slowdown allows bacteria to outlast the temporal window of antibiotic action, mimicking a dormant state [22; 28]. The principal molecular mechanisms underlying bacterial metabolic rewiring in response to antibiotics are summarized in Table 1.