Bacterial Metabolism and Antibiotic Efficacy

Abstract

Antibiotics target energy-consuming processes. As such, perturbations to bacterial metabolic homeostasis are significant consequences of treatment. Here, we describe three postulates that collectively define antibiotic efficacy in the context of bacterial metabolism: (1) antibiotics alter the metabolic state of bacteria, which contributes to the resulting death or stasis; (2) the metabolic state of bacteria influences their susceptibility to antibiotics; and (3) antibiotic efficacy can be enhanced by altering the metabolic state of bacteria. Altogether, we aim to emphasize the close relationship between bacterial metabolism and antibiotic efficacy as well as propose areas of exploration to develop novel antibiotics that optimally exploit bacterial metabolic networks.

Keywords: antibiotic adjuvants; antibiotic mechanism; antibiotic tolerance; bacterial metabolism.

Figure 1

Cellular Processes Targeted by Conventional Antibiotics Although a relatively large number of clinically available antibiotics have been developed, these collectively target a narrow spectrum of macromolecular biosynthetic processes. With few exceptions, target processes can be grouped into four primary categories: cell envelope biogenesis, DNA replication, transcription, and protein biosynthesis.

Figure 2

Models of the Metabolic Consequences of Treatment with Bactericidal and Bacteriostatic Antibiotics Primary target corruption by bactericidal antibiotics causes damage to essential macromolecules within the cell. This leads to the induction of stress response pathways to alleviate the deleterious consequences of the initial target corruption, which increases metabolic activity to meet the corresponding energy demands. The heightened metabolic output results in the production of toxic metabolic byproducts such as reactive species, which promiscuously damage macromolecules, leading to the induction of additional stress response pathways, thus once again increasing metabolic load. This process continues until the cycle terminates with bacterial cell death. Bacteriostatic antibiotics, on the other hand, tend to strictly inhibit protein biosynthesis (or transcription in certain contexts). This leads to a decrease in metabolic activity and subsequent cell stasis.

Figure 3

Repression Displayed by Antibiotic-Tolerant Bacteria Can Be Overcome through Multiple Emerging Approaches Antibiotic-tolerant bacteria—whether nutrient-limited stationary phase cells, persisters, or biofilms—all display repressed metabolism that contributes to their ability to survive bactericidal antibiotic treatment. Metabolic activation through the use of metabolite adjuvants has been shown to enhance the sensitivity of antibiotic-tolerant bacteria to conventional bactericidal antibiotics. Furthermore, molecules like polymyxins, human cationic peptides, and ADEP4 display bactericidal activity that is independent of the metabolic state of the cell and may represent a promising approach to develop antibiotics that are not impeded by metabolic repression displayed by conventionally antibiotic-tolerant populations. Lastly, engineered phage and bacteria that actively modulate the metabolic response of pathogens to conventional antibiotics may be an alternative approach to eradicate cells in metabolically repressed states.