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Pathogenic species have to deal with a wide range of environments both within and outside the host and most have elaborate regulatory circuits to ensure the correct temporal and spatial expression of virulence factors. However, in most cases the primary clues used by the bacteria to determine whether they are in the host and the mechanisms by which this sensing occurs are not well understood. Vibrio cholerae is the causative agent of the potentially lethal epidemic diarrheal disease cholera. Na+ -based bioenergetics plays an important role in both the environmental and infectious phases of this organism. We recently reported the first example for an intimate connection between the expression of the main virulence factors and the sodium membrane bioenergetics in V. cholerae. It is conceivable that changes in the chemiosmotic sodium cycle are the primary signals that this organism uses to determine whether it is in the extra-host environment or the human gut. The objective of our research is the detailed molecular characterization of the observed linkage between transmembrane Na+ circulation and virulence in V. cholerae. Our experimental design is based on the combination of methods of classical membrane bioenergetics with the powerful tools of modern molecular genetics. Such an interdisciplinary approach will yield results that would be vitally important not only for the case of V. cholerae but also for the better understanding of regulation of virulence in various pathogenic microorganisms.
The recent completion of many bacterial genome sequences revealed the presence of genes encoding various sodium-dependent systems in orgamisms, including some that were not known to have a primary sodium cycle of energy. Analysis of bacterial genome sequences shows that many human and animal pathogens encode primary membrane Na+ pumps 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 may well be an important virulence factor for some pathogens and could provide a target for development of a novel intervention strategy. Indeed, the recent discovery of an effective natural antibiotic, korormicin, targeted against the Na+-translocating NADH:ubiquinone oxidoreductase, NQR, suggests the potential use of Na+ pumps as a drug target. Moreover, anti-microbial potential of other inhibitors of the Na+ cycle, such as monensin, Li+ and Ag+ ions, and amiloride derivatives have been previously reported. During this project we intend to construct and analyze defined mutants in Na+-extruding enzymes in V. cholerae as a first step towards a better understanding of this complex system in bacteria. The long-term goal is to identify novel drug targets amongst these enzymes and develop a potentially new class of anti-infectives to combat bacterial infections by pathogens that utilize sodium as a coupling ion. V. cholerae represents one of the best model organism for a comprehensive and detailed analysis of the sodium cycle of energy, as it has been experimentally demonstrated to utilize Na+ as a coupling ion and appears to possess a multitude of Na+-dependent systems.
Hasegawa H, Häse CC. 2009. The extracellular metalloprotease of Vibrio tubiashii directly inhibits its extracellular hemolysin. Microbiol. 155: 2296-305.
Häse CC, Judson N, Mekalanos JJ. Cholera. In, Encyclopedia of Microbiology (J. Lederberg, ed), 2nd Edition, Academic Press, pp 143-154, 2000.
Barquera B, Hellwig P, Zhou W, Morgan JE, Häse CC, Gosink KK, Nilges M, Bruesehoff PJ, Roth A, Lancaster RCD et al.. 2002. Purification and characterization of the recombinant Na(+)-translocating NADH:quinone oxidoreductase from Vibrio cholerae.. Biochemistry. 41(11):3781-9.