Chapter 7 : Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria

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For prototrophic bacteria, central metabolism (i.e., glycolysis, the pentose phosphate pathway, and the Krebs cycle) supplies the 13 biosynthetic intermediates necessary to synthesize biomolecules ( Fig. 1 ). Gram-positive bacteria (i.e., Actinobacteria and Firmicutes) exhibit a diverse collection of central metabolic capabilities that have been shaped by reductive evolution. Some Gram-positive bacteria (e.g., and ) have complete central metabolic pathways, but others (e.g., and ) have Krebs cycle deficiencies, and some have multiple central metabolism deficiencies (e.g., and ). These differences in central metabolic capabilities are also reflected in the bacteria’s ability to persist away from a host organism; specifically, the more metabolically impaired the bacterium, the more dependent it is on its host. In essence, hosts serve as a reservoir for metabolites that overcome deficiencies in central and intermediary metabolism. Metabolic deficiencies are not created by only reductive evolution; they are also created when bacteria encounter stressful environments (e.g., iron limitation or a host immune response) that alter carbon flux ( ). These changes in flux alter the metabolome, which can modulate the activity of metabolite-responsive global regulators such as CodY, CcpA, Rex, and RpiR. In the first portion of this chapter, we discuss how genetic, environmental, and nutritional conditions alter the metabolome, primarily central metabolism, and in the second part, how these metabolic changes influence the activity of metabolite-responsive regulators. Finally, we discuss how metabolism and metabolite-responsive global regulators influence the outcomes of host-pathogen interactions. This review references only those manuscripts published through December 2013.

Citation: Richardson † A, Somerville † G, Sonenshein † A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, p 129-165. In Conway T, Cohen P (ed), Metabolism and Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MBP-0004-2014
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Figure 1

A simplified view of bacterial physiology. The 13 biosynthetic intermediates discussed in this chapter are all derived from the three metabolic pathways of central metabolism. Alterations in the availability of these biosynthetic intermediates always affect virulence factor synthesis.

Citation: Richardson † A, Somerville † G, Sonenshein † A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, p 129-165. In Conway T, Cohen P (ed), Metabolism and Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MBP-0004-2014
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Figure 2

Synergistic repression of toxin synthesis by CodY and CcpA. Responding independently to different nutritional signals, CcpA and CodY both bind to the regulatory region of the gene, repressing production of the alternative sigma factor necessary for high-level toxin gene ( and ) expression.

Citation: Richardson † A, Somerville † G, Sonenshein † A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, p 129-165. In Conway T, Cohen P (ed), Metabolism and Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MBP-0004-2014
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Figure 3

Examples of oxidative and reductive metabolic pathways in . NADH produced during glycolysis and other oxidative pathways is converted back to NAD by a series of reductive pathways. The proline pathway, catalyzed by proline reductase, appears to be the favored pathway. When proline is available, the other pathways shown are repressed by Rex. Repression by Rex is relieved when the ratio of NAD to NADH indicates the need for increased regeneration of NAD. Additional repression by CcpA and CodY restricts maximal expression of the alternative pathways to conditions in which CcpA and CodY are relatively inactive. The bottom three pathways (effectively, acetyl-CoA to butyrate) are encoded in a single eight-gene operon.

Citation: Richardson † A, Somerville † G, Sonenshein † A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, p 129-165. In Conway T, Cohen P (ed), Metabolism and Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MBP-0004-2014
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Figure 4

Differences in M1- versus M2-macrophage fueling reactions. In response to inflammatory stimuli, M1-macrophages upregulate a pathway known as aerobic glycolysis. This involves the import of glucose through GLUT-1 and its phosphorylation by Hexokinase-1 (HK-1). The resulting glucose-6-phosphate (G6P) can be shuttled through the pentose phosphate pathway (PPP) for NADPH generation, which fuels immune radical production, including nitric oxide (NO). At the same time, G6P is also oxidized to pyruvate (PYR) for ATP synthesis, and this PYR is primarily reduced to lactate (LAC) to conserve redox balance. Very little PYR enters the Krebs cycle as acetyl-CoA (Ac-CoA) due to the phosphorylation and inactivation of pyruvate dehydrogenase (PDH). Genes activated/repressed by HIF-1α are depicted as green/red. Upon stimulation with anti-inflammatory stimuli, M2-macrophages adopt an oxidative metabolism involving the import of free fatty acids and low-density lipoprotein (LDL)-associated lipids (fatty acids and LDL) by CD36. These fatty acids are linked to carnitine and shuttled to the mitochondria for β-oxidation, yielding ATP. In addition, some of the Ac-CoA is reused to synthesize new fatty acids. Rather than using tissue arginine for NO-production, these cells use the amino acid for proline and polyamine production, the former of which is critical for collagen synthesis. Features activated/repressed by PPAR-γ are depicted in green/red.

Citation: Richardson † A, Somerville † G, Sonenshein † A. 2015. Regulating the Intersection of Metabolism and Pathogenesis in Gram-positive Bacteria, p 129-165. In Conway T, Cohen P (ed), Metabolism and Bacterial Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MBP-0004-2014
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