Revisiting the host as a growth medium

Abstract

The ability of the human body to play host to bacterial pathogens has been studied for more than 200 years. Successful pathogenesis relies on the ability to acquire the nutrients that are necessary for growth and survival, yet relatively little is understood about the in vivo physiology and metabolism of most human pathogens. This Review discusses how in vivo carbon sources can affect disease and highlights the concept that carbon metabolic pathways provide viable targets for antibiotic development.

Figure 1. Molecular mimicry by Neisseria meningitidis

a Glucose catabolism in N. meningitidis proceeds by the Entner–Doudoroff pathway and lactate catabolism feeds directly into the sialic acid pathway. Note the relative number of metabolic steps from glucose to phosphoenolpyruvate compared with that from lactate to phosphoenolpyruvate. b Sialylated lipopolysaccharide (LPS) on the N. meningitidis surface mimics the surface of eukaryotic cells, preventing deposition of the complement molecule C3. Inactivation of the lactate permease gene lctP results in C3-mediated cell lysis.

Figure 2. Mycobacterium tuberculosis cholesterol catabolism and virulence factor production

A proposed pathway for cholesterol catabolism with relevant gene products has recently been published for the soil bacterium Rhodococcus sp. strain RHA1 (Ref. 115). M. tuberculosis possesses homologues for almost all of the genes involved in cholesterol degradation, several of which are important for intracellular growth. However, definitive M. tuberculosis use of cholesterol as a sole source of carbon and energy was reported only recently, and in this study radioactive labelling was used to demonstrate the differential fates of cholesterol carbons. A labelled side-chain carbon (shown in red) was incorporated into the virulence lipid phthiocerol dimycocerosate, presumably by conversion of side-chain-derived propionyl-CoA to methylmalonyl-CoA, a precursor to phthiocerol dimycocerosate and other virulence lipids. Successive oxidation of the remaining side chain produces an acetyl-CoA and an additional propionyl-CoA moiety (not shown). Conversely, a labelled ring carbon (shown in green) was released as CO₂, indicating that this carbon enters the tricarboxylic acid (TCA) cycle and is mineralized. Some aspects of M. tuberculosis cholesterol catabolism remain unclear, including the fates of the degradation product 9,17-dioxo-1,2,3,4,10,19-hexanorandrostan-5-oic acid (DOHNAA) and propionyl-CoA moieties produced through ring cleavage and successive side chain degradation.

Figure 3. Resource partitioning by oral bacteria

The figure shows a view of the microbial community that inhabits the gingival crevice, which is the space between the tooth and gum. Gingival crevicular fluid, which is similar in composition to serum, contains millimolar concentrations of glucose and lactate and micromolar concentrations of other phosphotransferase system (PTS) sugars. Streptococcus species (green circles) within the gingival crevice rapidly consume sugars (hexagons) and produce lactate (yellow squares). Despite constitutive expression of PTS sugar and lactate catabolic genes, Aggregatibacter actinomycetemcomitans (blue rods) preferentially uses lactate. Lactate metabolism by the lactate dehydrogenase enzyme results in a rapid increase in intracellular pyruvate levels which is hypothesized to inhibit glucose transport or metabolism by A. actinomycetemcomitans through an unknown post-transcriptional mechanism.

Figure 4. Cell–cell communication, carbon metabolism and pathogenesis in Pseudomonas aeruginosa

a A simplified view of the fates of chorismate in P. aeruginosa. Chorismate, the biosynthetic precursor of the aromatic amino acids tyrosine (Tyr), phenylalanine (Phe) and tryptophan (Trp), is synthesized from the central metabolites erythrose-4-phosphate and phosphoenolpyruvate. Chorismate synthesis is a highly regulated process in Escherichia coli but might be constitutive in P. aeruginosa. In addition to the aromatic amino acids, chorismate is also the biosynthetic precursor of 2-heptyl-3-hydroxy-4-quinolone, a cell–cell signal that is unique to P. aeruginosa (the Pseudomonas quinolone signal; PQS). b A model for the impact of aroxmatic amino acids on P. aeruginosa physiology during cystic fibrosis (CF) lung infection. High levels of aromatic amino acids are present in CF sputum. P. aeruginosa scavenges these amino acids for protein synthesis, thereby diverting intracellular chorismate pools to PQS biosynthesis. PQS induces virulence factor production including the blue-green phenazine pigment pyocyanin^,, hydrogen cyanide (HCN) and toxin-loaded membrane vesicles (MVs) (+Aro). In the second scenario, depletion of aromatic amino acids from the CF lung (potentially by some novel therapeutic), forces P. aeruginosa to use intracellular chorismate pools to support protein biosynthesis (−Aro). In turn, production of PQS and PQS-regulated virulence factors decreases.