## 3 Metabolic Responses to Different Antibiotic Classes
### Krebs Cycle and Glyoxylate Shunt: Carbon-Sparing Survival  
The tricarboxylic acid (TCA) cycle serves as a central hub for energy generation and biosynthetic precursors [76]. However, several of its enzymes--such as aconitase, succinate dehydrogenase, and \(\alpha\)-ketoglutate dehydrogenase--contain Fe-S clusters that are highly sensitive to oxidative stress [77]. During antibiotic exposure, bacteria may suppress or restructure the TCA cycle to limit the production of reactive oxygen species (ROS). This metabolic shift is exemplified by the transition from TCA cycle-driven energy metabolism to alternative pathways, such as the glyoxylate shunt and lactate fermentation, which support bacterial quiescence and tolerance during antibiotic stress (Figure 3). These adaptations enable carbon conservation and the reduction of oxidative stress, contributing to survival under adverse conditions. \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Metabolic Node** & **Adaptive Change** & **Functional Outcome** & **References** \\ \hline Pyruvate Flux & Shift to lactate/acetate fermentation & NAD\({}^{+}\) regeneration, ROS reduction, ATP from substrate-level phosphorylation & [70; 71; 72; 73] \\ \hline Respiration & Suppression under antibiotic stress & Decreased ROS production & [70; 71; 72] \\ \hline NAD\({}^{+}\)/NADH Balance & Restoration via fermentative pathways & Maintains redox homeostasis & [70; 71; 72; 73] \\ \hline Regulatory Systems & Activation of SrrAB, NreBC & Controls fermentative gene expression & [74; 75] \\ \hline \hline \end{tabular} NAD\({}^{+}\): nicotinamide adenine dinucleotide; ROS: reactive oxygen species.  
\end{table} 
Table 4: Glycolysis and fermentative reprogramming under antibiotic stress. This metabolic modulation reduces intracellular oxidative stress, contributing to antibiotic tolerance and survival in hostile environments [78; 79]. In response to oxidative stress or limited nutrient availability, many pathogenic bacteria activate the glyoxylate shunt, a variant of the TCA cycle [80]. This pathway, mediated by the enzymes isocitrate lyase and malate synthase, allows bypass of oxidative decarboxylation reactions, thus avoiding carbon loss in the form of CO\({}_{2}\)[80]. This metabolic adaptation enables carbon conservation and the generation of essential biosynthetic intermediates, thereby supporting pathogen survival under hostile conditions and during host infection [81]. In _Mycobacterium tuberculosis_, activation of the glyoxylate cycle--catalyzed by isocitrate lyase and malate synthase--is essential for intracellular survival during the latent phase of infection [82; 83]. This adaptation allows _M. tuberculosis_ to evade the oxidative decarboxylation steps of the TCA cycle, preserving carbon and generating key intermediates for gluconeogenesis and macromolecular biosynthesis [84]. Central metabolic reconfiguration in _M. tuberculosis_, characterized by suppression of oxidative respiration and activation of the glyoxylate cycle, supports pathogen persistence in the hostile microenvironments typical of latent infection [85]. This adaptation limits intracellular ROS generation, contributing to drug tolerance and survival in the presence of bactericidal antibiotics [82]. This metabolic rerouting, involving suppression of the TCA cycle and redirection of carbon flux through the glyoxylate shunt and fermentative pathways, exemplifies the adaptive strategy that supports bacterial survival under antibiotic stress (Figure 4). Enzymes such as succinate dehydrogenase and isocitrate lyase play key regulatory roles in this transition, mediating a shift toward carbon-efficient and redox-balanced states. Figure 3: Metabolic adaptation of bacteria under antibiotic stress involves a transition from active energy metabolism, predominantly driven by the tricarboxylic acid (TCA) cycle, to alternative, low-energy states that support survival. Under normal conditions, glucose metabolism fuels the TCA cycle to generate ATP.