Sodium ion cycle in bacterial pathogens: evidence from cross-genome comparisons

Abstract

Analysis of the bacterial genome sequences shows that many human and animal pathogens encode primary membrane Na+ pumps, Na+-transporting dicarboxylate decarboxylases or Na+ translocating NADH:ubiquinone oxidoreductase, and a number of Na+ -dependent permeases. This indicates that these bacteria can utilize Na+ as a coupling ion instead of or in addition to the H+ cycle. This capability to use a Na+ cycle might be an important virulence factor for such pathogens as Vibrio cholerae, Neisseria meningitidis, Salmonella enterica serovar Typhi, and Yersinia pestis. In Treponema pallidum, Chlamydia trachomatis, and Chlamydia pneumoniae, the Na+ gradient may well be the only energy source for secondary transport. A survey of preliminary genome sequences of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, and Treponema denticola indicates that these oral pathogens also rely on the Na+ cycle for at least part of their energy metabolism. The possible roles of the Na+ cycling in the energy metabolism and pathogenicity of these organisms are reviewed. The recent discovery of an effective natural antibiotic, korormicin, targeted against the Na+ -translocating NADH:ubiquinone oxidoreductase, suggests a potential use of Na+ pumps as drug targets and/or vaccine candidates. The antimicrobial potential of other inhibitors of the Na+ cycle, such as monensin, Li+ and Ag+ ions, and amiloride derivatives, is discussed.

FIG. 1

Proton and sodium ion cycles in bacterial energetics. “Primary pump” indicates any proton or sodium motive force generator (e.g., respiratory ion pump, membrane ATPase, or a Na⁺-transporting dicarboxylate decarboxylase). “H⁺ (or Na⁺) porter” indicates consumers of proton (or sodium) motive force (symporters, flagellar motor, etc.). The actual presence of partial components of both cycles in the membrane of each particular bacterial species may vary, depending on the physiological state of the cell. Na⁺/H⁺ antiporters convert proton motive force into sodium motive force and vice versa, playing an important role in cell homeostasis.

FIG. 2

Phylogenetic distribution of the bacterial pathogens that use the Na⁺ cycle. The dendrogram shows the taxonomic positions of the organisms with completely sequenced genomes and several pathogens discussed in the text, according to the NCBI Taxonomy database (http://www.ncbi/nlm.nih.gov/Taxonomy) (218). The branches indicate taxonomic relations only; their lengths do not necessarily reflect evolutionary distances. The main bacterial phyla are shown in boldface. Bacterial species that appear to utilize the Na⁺ cycle are shaded.

FIG. 3

Domain organization of a new type of sensor histidine kinases. SMART (175) diagrams of the common domain structure V. cholerae protein VC0303 and P. aeruginosa proteins PA3271 and PA4725 (A) and R. prowazekii protein RP465 (B). (A) The small open box on the left indicates the likely signal peptide, predicted by the SignalP program (144). The vertical boxes indicate 12 transmembrane helices of the solute/sodium symporter family (TC 2.A.21) transporter, predicted by the TopPred program (29). The circle indicates the PAS domain (198); the two hexagons indicate the phosphoacceptor and ATPase domains, respectively, of the histidine kinase; and the dotted square on the right indicates the CheY-type receiver domain (193). (B) R. prowazekii protein RP465 contains 16 predicted transmembrane helices and both domains of a histidine kinase but lacks PAS and CheY-type domains. The ruler indicates the length of the protein in amino acid residues.

FIG. 4

Scheme of the Na⁺-dependent citrate fermentation pathway. Citrate is transported into the cell in symport with Na⁺ ions by CitS (step 1) and split into acetate and oxaloacetate by citrate lyase CitDEF (step 2). Decarboxylation of oxaloacetate into pyruvate by Na⁺-transporting oxaloacetate decarboxylase, OadGAB (step 3), restores the Na⁺ gradient and produces pyruvate. Pyruvate-formate lyase PflD splits pyruvate into formate and acetyl-CoA (step 4), which is further converted into acetylphosphate by phosphotransacetylase Pta (step 5). Dephosphorylation of acetylphosphate by acetate kinase AckA (step 6) yields ATP, resulting in energy conservation. The enzymes are indicated by their standard gene names, where available. The fermentation end products are boxed. See reference for more details.

FIG. 5

Structures of some inhibitors of the Na⁺ cycle. (A) Korormicin. (B) 2-n-Heptyl-4-hydroxyquinoline N-oxide (HQNO). (C) Monensin. (D) Amiloride.