## 3 Metabolic Responses to Different Antibiotic Classes
### Membrane Biosynthesis and Lipid Adaptations  
Bacterial membranes constitute a dynamic barrier whose composition and biophysical state significantly influence antibiotic uptake [99].  
In Gram-negative bacteria, the outer membrane restricts the entry of many antibiotics, with permeability modulated by lipid composition and porin expression [100].  
Membrane fluidity--determined by factors such as fatty acid composition and ambient temperature--profoundly affects the passive diffusion of lipophilic antibiotics across the phospholipid bilayer [101; 102].  
Alterations in fluidity serve as an adaptive strategy to modulate selective permeability [102].  
Additionally, many antibiotics exert direct effects on the membrane by interacting with lipid components, inducing structural reorganizations that compromise barrier integrity and facilitate drug penetration [103].  
In response to exposure to polycationic drugs, such as aminoglycos and colistin, bacteria implement lipid composition adjustments to mitigate the toxic effects of these antibiotics [104].  
These modifications include the increased incorporation of branched and saturated fatty acids, which reduce membrane fluidity and limit antibiotic penetration; the incorporation of amino groups such as 4-amino-4-deoxy-L-arabinose into LPS, thereby decreasing the net negative charge of the outer membrane and reducing affinity for cationic antibiotics; and the accumulation of triacylglycerlecrols in intracellular vesicles, which may serve as energy reserves and contribute to antibiotic tolerance [104; 105; 106].  
Bacterial membrane adaptations, regulated by the two-component systems PhoPQ and PmrAB, represent critical strategies for survival in hostile environments and under antibiotic pressure [107].  
These systems coordinate the synthesis of lipid enzymes and transporters that alter membrane composition, influencing permeability and the electrochemical potential [108].  
Such modifications can impair antibiotic uptake efficiency, compromising their effectiveness [108].  
Interaction with the Host and Microbiota: Ecological Dynamics, Adaptive Niches, and Immunometabolic Signals  
The metabolic reprogramming of bacterial pathogens does not occur in a biochemical vacuum but rather unfolds within complex and dynamic ecosystems dominated by interactions among the bacterium, the host, and the commensal microbiota [109; 110].  
In this context, antibiotics and environmental signals act both as selective pressures and as stimuli for metabolic restructuring in bacterial pathogens, promoting the emergence of adaptive phenotypes closely linked to survival within host microenvironments [111].  
\begin{table}
\begin{tabular}{c c c c} \hline
**Pathway Component** & **Stress-Driven Change** & **Adaptive Benefit** & **References** \\ \hline \multirow{2}{*}{Aconitase, SDH, \(\alpha\)-KGDH} & \multirow{2}{*}{\begin{tabular}{c} Suppressed due to Fe–S cluster \\ sensitivity to ROS \\ \end{tabular} } & \multirow{2}{*}{\
\begin{tabular}{c} Reduces oxidative damage \\ \end{tabular} } & [77; 78; 79] \\ \hline \multirow{2}{*}{TCA Cycle} & \multirow{2}{*}{
\begin{tabular}{c} Downregulated in \\ hostile environments \\ \end{tabular} } & \multirow{2}{*}{Limits ROS, slows metabolism} & [78; 79] \\ \hline \multirow{2}{*}{Glyoxylate Shunt} & Activated via isocitrate lyase & Carbon conservation, evasion of \\  & and malate synthase & CO\({}_{2}\) loss & [80; 81; 82; 83; 84; 85] \\ \hline \multirow{2}{*}{_Mycobacterium tuberculosis_} & Relies on glyoxylate shunt & Supports survival under \\  & during latency & immune and antibiotic stress & [82; 83; 84; 85] \\ \hline \end{tabular}  
* SDH: succinate dehydrogenase; \(\alpha\)-KGDH: alpha-ketoglutate dehydrogenase; CO\({}_{2}\): carbon dioxide.  
\end{table}
Table 6: TCA cycle modulation and glyoxylate shunt activation in antibiotic adaptation.  
These stimuli induce changes in bacterial metabolic and morphological pathways, facilitating adaptation to hostile conditions and contributing to infection persistence [112].